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*all ‘averages’ mentioned are based on a 70kg male

The GI Tract

Week 1

Function

• Acquires nutrients from environment
• Anabolism: Uses raw materials to synthesize essential compounds
• Catabolism: Decomposes substances to provide energy cells need to functionwe
  • *need O2 and organic molecules (macronutrients) that can be broken down by intracellular enzymes

 

Six Main Actions of the GI System

1. Ingestion: Occurs when food or fluid enters the mouth

2. Mechanical Processing: Crushing / Shearing –makes material easier to move through the tract

3. Secretion: Release of water, acids, buffers, enzymes & salts by epithelium of GI tract (the inside skin of the GI tract) and glandular organs

4. Digestion: Chemical breakdown of food (macronutrients) into small organic compounds for absorption

5. Absorption: Movement of organic substrates, electrolytes, vitamins & water across digestive epithelium

6. Excretion: Removal of waste products from body fluids

Functions of Oral Cavity

• Sensory analysis of material before swallowing
• Mechanical processing: Through actions of teeth, tongue, and palatal surfaces
  • The soft palate sits further back into the mouth and is more pliable so when you swallow the bolus goes down easier.
• Lubrication: Mixing with mucus and salivary gland secretions
  • 3 pairs of salivary glands
  • 1-1.5L of saliva per day on average (99.4% water) 0.6% = electrolytes, buffers, glycoproteins, antibodies and enzymes
• Limited digestion: Carbohydrates and lipids
  • Salivary Amalyase: breaks down starch into small polysaccharides
  • Lingual Lipase: preliminary breakdown of lipids
    • Lingual = side of tongue 

Esophagus

• A hollow muscular tube with a sphincter at each end
• About 25 cm long and 2 cm wide
• Conveys solid food and liquids to the stomach

3 Phases to Swallowing:

1. Buccal Phase: Voluntarily swallowing: tongue forces food to the back of the mouth
2. Pharyngeal Phase: First involuntary phase – epiglottis folds down and the pharynx comes up to block the trachea
3. Esophageal Phase: Peristalis pushing food down

Peristalsis

Contraction of smooth muscles behind bolus of food to push it forward and muscles ahead of it relax except longitudinal muscles that assist pushing it forward

Stomach Function

• Storage of ingested food
• Mechanical breakdown of ingested food (chyme) through the churning of the chyme
• Disruption of chemical bonds in food material by acid and enzymes
• Production of intrinsic factor, a glycoprotein required for absorption of vitamin B12 in small intestine
  • Important for people who have had stomach surgery are likely to have reduced ability to produce IF so keeping watch of IF levels is critical

Gastric Anatomy

• Pyloric sphincter controls the rate of stomach emptying into the SI
• The integrity of the stomach lining is being constantly repaired and protected by mucous against the acidic environment
• Fundus and body contain gastric glands that contain chief cells (produce HCL/pepsinogen) and parietal cells (produce HCL/IF)
  • Pepsinogen is a inactive pro-enzyme (the active form is pepsin)

Digestion in the Stomach

• Stomach performs preliminary digestion of proteins by pepsin (the active form of pepsinogen):
• Some pre-digestion of carbohydrates (by salivary amylase in the mouth)
  • Once food enters the stomach, stomach acids inactive salivary amylase
• Lipids (by lingual lipase)
• 10% of energy is lost from available energy in food arising from the digestion and absorption costs of processing the food

Stomach contents

• Become more fluid
• pH approaches 2.0 during digestion (resting pH = 5-6 / neutral pH = 7)
• Pepsin activity increases and protein disassembly begins
• Although digestion occurs in the stomach, nutrients are not absorbed there

Small Intestine

90% of absorption occurs in the small intestine

Intestinal Secretions Help:

• Secrete watery intestinal juice into the SI
• 1.8 litres per day enter intestinal lumen which helps moisten chyme and adds accessibility for enzymes to assist with digestion and absorption 
• Assists in buffering acids and increase the pH to a more neutral 6-7~
• Keep digestive enzymes and products of digestion in solution where they’re far more accessible

The Duodenum

• The smallest segment of small intestine closest to stomach (25 cm long)
• Primary role = coordinate release of enzyms and buffers from pancreas and liver 
• Receives chyme from stomach and digestive secretions from pancreas and liver
• Neutralizes acids before they can damage the absorptive surfaces of the small intestine
• Releases Secretin: Stimulated via the S cells on the duodenum epithelium to secrete bicarbonate (HCO3) to buffer the acidity of the SI
• Releases CCK: Stimulates the release of bile in the duodenum via the gallbladder
• Nutrient Absorption: Iron and CA

The Jejunum

Is the middle segment of small intestine ‐ 2.5 metres  long

Is the location of most:

• Chemical digestion
• Nutrient absorption
  • The nutrients enter the enterohepatic system.
  • Those nutrients will enter the liver to be processed/detoxify first before they are transported anywhere for use
  • CA, B-Vitamins, Fat Soluable Vitamins, Water Soluable Vitamins
  • Performed via small villi which increase surface area of the SI and form the brush border. Increasing surface area increases absorptive capacity.
  • Microvilli are microscopic cellular membrane protrusions that increase the surface area of cells for diffusion and minimize any increase in volume, and are involved in a wide variety of functions, including absorption, secretion, cellular adhesion, and mechanotransduction.
  • Lacteals: The exception are lipids which are absorbed differently through the lacteals located inside the villi.

Villi vs Microvilli:

• Villi = The small finger like projections of the small intestine
• Microvilli: In the small intestine there are finger-like projections (villi) and on these finger-like projections are even smaller finger-like projections. These even smaller finger-like projections are called micro villi.

 

The Ileum

• The final segment of small intestine ‐ 3.5 metres long
• Ends at the ileocecal valve, a sphincter that controls flow of material from the ileum into the large intestine
• Absorb VB12 from intrinsic factor via the production of intrinsic factor in the stomach and absorbs bile salts.
• Secretes enzymes that are responsible from the final stages of PRO and CHO absorption.

Large Intestine

• So the small intestine has digested and absorbed everything, right? Not quite…enter the large intestine. Absorption occurs here also, just not to the same extent as the small intestine.
• And whilst absorption of some nutrients does occur in the large intestine, its major function is that of the re-absorption of water, bile salts and the compaction of the remaining intestinal contents into faeces.

Structure

• Is horseshoe shaped
• Extends from end of ileum at the ileocecal valve to anus
• Lies inferior to stomach and liver
• Frames the small intestine
• Also called large bowel
• Is about 1.5 metres long and 7.5 cm wide

Function:

1. Reabsorption of water
   1. Dry/hard stools difficult to pass through can be a sign of dehydration
2. Compaction of intestinal contents into faeces
3. Absorption of important vitamins produced by bacteria
4. Reabsorb bile salts in the cecum
5. Storage of faecal material prior to defecation

Components of the Large Intestine

The Cecum

• Is an expanded pouch
• Receives material arriving from the SI/ileum
• Stores materials and begins compaction

The Colon

• Has a larger diameter and thinner wall than small intestine
• Because its primary role is water absorption it doesn’t need those villi
• The wall of the colon: Forms a series of pouches (haustra) Haustra permit expansion and elongation of colon

Ascending Colon

• Begins at superior border of cecum
• Ascends along right lateral and posterior wall of peritoneal cavity to inferior surface of the liver and bends at right colic flexure (hepatic flexure)

Transverse Colon

• Crosses abdomen from right to left; turns at left colic flexure (splenic flexure)

The Descending Colon

• Proceeds inferiorly along left side to the iliac fossa (hip bone)
• Is behind the peritoneum & firmly attached to abdominal wall which is why abdominal injuries can frequently cause LI  injuries

Sigmoid

• Is an S‐shaped segment, about 15 cm (6 in.) long
• Starts at sigmoid flexure Lies behind the bladder
• Empties into rectum

The Rectum

• Forms last 15 cm of digestive tract
• Is an expandable organ for temporary storage of faeces
• Movement of faecal material into rectum triggers urge to defecate

Movements of the Large Intestine

• Gastroileal & gastroenteric reflexes move materials into cecum while you eat
• Movement from cecum to transverse colon is very slow, allowing hours for water absorption
• Peristaltic waves move material along length of colon
• Segmentation movements (haustral churning) mix contents of adjacent haustra
• Movements from transverse colon through rest of large intestine results from powerful peristaltic contractions (mass movements)
• Stimulus for that is the distension of stomach and duodenum; relayed over intestinal nerve plexuses
• Distension of the rectal wall triggers defecation reflex
• Two positive feedback loops: Both loops triggered by stretch receptors in rectum

Physiology of the Large Intestine

• Reabsorption of water
• Reabsorption of bile salts
  • In the cecum
  • Transported in blood to liver
• The nutrient absorption that we do have in the LI is from the vitamins that are produced by bacteria
• Conversion and excretion of organic wastes

Three Vitamins Produced in the Large Intestine

#Exam

1. Vitamin K (fat soluble):

• Required by liver for synthesizing four blood clotting factors
• Infants are given a Vitamin K shot because they don’t have the gut bacteria that produce Vitamin K because they’re LI hasn’t matured and populated fully with bacteria

2. Biotin (water-soluble):

• Important for fatty acid synthesis
• Breaks down BCAA’s
• Important for gluconeogenesis

3. Patothenic acid: B5 (water soluble):

• Required in the synthesis of steroid hormones and some neurotransmitters like coenzyme-A

Organic Wastes

• Bilirubin is the yellow by-product of the breakdown of old RBCs. Bacteria convert this to urobilinogen and then further to stercobilin which is brown, hence the colour of faeces. [Why stool is brown]
• Bacteria break down peptides in faeces
• Bacteria feed on indigestible carbohydrates (complex polysaccharides) which produce flatus, or intestinal gas, in large intestine
  • If simple CHO (monosaccharides & disaccharides) make it down to the LI which doesn’t usually happen the bacteria feed on them and produce more gas (sounds linked to SIBO where bacteria migrate up from LI to SI and feed on sugar)
  • If we consume too much simple CHO LI will attempt to flush it out. Common in kids who consume too much sugar and develop toddler diarrhea.
  • Some foods contain higher amounts of indigestable CHO than others such as onions and vetagables from brassica species (green leafy vegatbles) that can also contribute to gas.

The GI Tract – Summary

• Mouth ‐ site of physical breakdown
• Stomach ‐ site of churning/mixing
• Small intestine – site of majority of absorption
• Large intestine – site of reabsorption of water, production of 3 vitamins, compaction and production of faeces

 

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The Liver and Biliary System

Week 2

The Liver

Summary Liver Function:

The liver regulates the composition of circulating blood. It can do this because of the blood leaving the absorptive surfaces of the GI tract . This blood enters the hepatic portal vein giving the liver access to all nutrients and toxins. The liver can then store or excrete excess nutrients. The liver can also synthesis plasma proteins , remove circulating hormones as well as antibodies. Finally, the liver can synthesise and secrete bile.

Summary Liver Metabolism: 

The liver is the principal site of synthesis of all circulating proteins. Blood plasma contains 60-80g/L of protein mainly in the form of albumin, globulin and fibrinogen. The liver also produces transport (or carrier) proteins – an example of which is transferrin. Coagulation proteins are also synthesised by the liver such as fibrinogen, prothrombin and numerous blood factors. Additionally, the liver receives degraded amino acids in the form of ammonia which are converted and excreted by the kidnesys in urine in the form of urea.

• Largest internal organ in the body (~1.5 Kg)
• Under the diaphragm, within the rib cage in the upper portion of the abdomen skewed to the right

Function:

• 200+ functions
• Related to all biochemical pathways related to growth
• Storage of CHO (as glycogen), fats (as lipoprotein/tryglycerdies)
• Circulates and synthesises protein to be used
• Detoxification
• Bile production
• Immune system support
• Supply of nutrients
• Aids Reproduction

 

Remember there’s 4 lobs of the liver

Blood Supplies

It’s the only organ that has two blood supplies: hepatic portal vein and the left hepatic vein

The Portal Vein (Portal Venous System):

Allows nutrient rich blood flow from the GI tract and the spleen to come to the liver to allow nutrient extraction and detoxification. *Why liver detoxication function is so important. 

The Hepatic Artery 

Carries oxygen rich blood to the liver from the lungs

The Left Hepatic Vein

Where livers deoxygenated/nutrient poor blood and already filtered blood goes back to the heart to be reoxygenated to then go back to the GI tract and repeat the process.

Liver Function

*one of the most important organs in the body

Metabolic Regulation

The liver regulates:

1. Composition of circulating blood
2. Nutrient metabolism (carbohydrate, lipid & amino acid)
3. Waste/toxin product removal
4. Vitamin Storage (A, D, E & K) *fat soluble
5. Mineral storage (iron)

Composition of Circulating Blood

All blood leaving absorptive surfaces of digestive tract:

• Enters hepatic (liver) portal system (portal vein)
• Flows into the liver to give access to nutrients and toxins

*Why mitigating toxins from food like pesticides is beneficial for your liver because it doesn’t have to work as much to detoxify if you’ve taken steps to mitigate toxins

• Liver cells extract nutrients or toxins from blood before they reach systemic circulation through the hepatic veins
• Liver removes and stores excess nutrients
• Corrects nutrient deficiencies by mobilizing stored reserves or performing synthetic activities

Hematological Regulation

• Largest blood reservoir in the body
• Receives 25% of cardiac output over 24h

Functions of Hematological Regulation

1. Phagocytosis and antigen presentation (removal and destruction of old dead RBCs)
2. Synthesis of plasma proteins (albumin which controls osmotic concentration)
3. Removal of circulating hormones (adrenalin, noradrenalin, TH)
4. Removal of antibodies (converted to amino acids for further use)
5. Removal or storage of toxins (often lipid soluable breaking down into water soluable)
6. Synthesis and secretion of bile

The Functions of Bile (Liver Creates)

• Dietary lipids are not water soluble
• Mechanical processing in stomach creates large droplets containing lipids
• Pancreatic lipase is not lipid soluble so it only interacts at the surface of the lipid droplet, hence we need bile to further break it down
• Produces 500ml-1000ml per day
• Bile salts break fat droplets apart (emulsification) analogous to soap breaking down oil on a pan
• By breaking down the lipid droplets into smaller versions you increase the surface area that is exposed to enzymatic attack
• The end products are tiny emulsion droplets coated with bile salts that are far more open to enzmatic attack for absorption

Gallbladder (Stores Bile)

Bile ducts from the liver converge to form the common hepatic duct, from which branches the ductleading to the gallbladder. Beyond this branch, the common hepatic duct becomes the common bile duct. The common bileduct and the main pancreatic duct converge and empty their contents into the duodenum at the sphincter of Oddi. Somepeople have an accessory pancreatic duct.

• Is a pear‐shaped, muscular sac
• Stores and concentrates bile prior to excretion into small intestine (duodenum) upon fat arriving from a meal via stimulation of cholecystokinin (CCK) hormone.
• Bile acts to emulsify and suspend fats in water so enzymes can breakdown the fats into smaller particles for absorption by the lacteals. 
• The Cystic Duct
  • extends from gallbladder
  • joins with common hepatic duct to form  common bile duct
• Gallbladder contains 40-70ml of bile.
• If bile is not ejected it becomes more concentrated

CCK: Cholecystokinin

• Peptide hormone (derived from CHOL made of proteins)
• CCK stimulates the release of bile from the gallbladder
• In the absence of CCK the hepatopancreatic sphincter remains closed which means Bile exiting liver in common hepatic duct cannot flow through common bile duct into duodenum
  • hepatopancreatic sphincter opens in the prescence of CCK in the duodenum
• Bile enters cystic duct and is stored in gallbladder

Exam Prep: Remember This

1. Food in stomach causes release of peptide hormone Gastrin which stimulates HCL, pepsin and increased gut motility.
   • The release of Gastrin inhibits Gastric Inhibitory Peptide (GIP). It’s not until chyme enters the duodenum that GIP is released. GIP stimulates the release of insulin from the pancreas.
2. Chyme entering the duodenum stimulates:
   • Secretin which stimulates buffers (HCO3) into to the duodenum which reduces the acidity to maintain optimal pH
     •  It also stimulates bile production by the liver; the bile emulsifies dietary fats in the duodenum so that pancreatic lipase can act upon them.
   • CCK – when chyme contains lipids and proteins, it accelerates pancreatic production of digestive enzymes and relaxes the hepatic-pancreatic sphincter to allow bile to flow
3. Vasoactive Intestinal Peptide (VIP): stimulates the dilation of intestinal capiliers to facilitate nutrient absorption and inhibits stomach acid production.
4. Chyme arrives in jejunum and further nutrient absorption is facilitated

Intestinal Absorption

• Takes about 5 hours for materials
  to pass from duodenum to end of ileum
• Movements of the mucosa increase absorptive effectiveness

Liver Synthesis

Protein metabolism:

You cannot make protein unless you eat protein. Amino acids being the building blocks of protein.

• Synthesis of amino acids
• The liver is the principal site of synthesis of all circulating proteins
• Plasma contains 60g-80 g/L of protein, mainly in the form of albumin (protein that helps regulate blood volume and osmotic pressure and is sensitive to fluid shifts), globulin (immune function) and fibrinogen (blood coagulation) which float around in the blood until they are retrived by the liver to be broken down or used for other molecules.
• Involved in the production of transport of carrier proteins such as transferrin (main iron transport protein)
• The liver also synthesizes all factors involved in coagulation
• The liver receives degraded amino acids (ammonia) which are converted to urea and excreted by kidneys.
  • Those with chronic liver disease need to take laxatives to force diarrhea to mitigate the build-up of ammonia which causes encephalopathy

• Net muscle protein synthesis is the difference between protein synthesis and degredation
• Between meals we have degradation (oxidation, catabolism) of protein  – it’s constantly being created and degraded

Carbohydrate metabolism

Glucose vs Glycogen: If you think of glucose as an individual unit molecule (a monosaccharide), glycogen is just lots of those glucose units stuck together as a polysaccharide to be stored away.

• Gluconeogenesis: the creation of CHO from non-CHO substrates. Sources for gluconeogenesis are lactate, pyruvate, amino acids from muscles (mainly alanine and glutamine) and glycerol from lipolysis of fat stores.
• In prolonged fasting, ketone bodies (produced by the liver from fatty acids) and fatty acids are used as alternative sources of fuel as the body tissues adapt to a lower glucose requirement
  • Gluco = glucose
  • Neo = new
  • Genesis = creation
• Glycogenolysis: the breakdown of stored glycogen into glucose.
  • Genolysis = Breakdown

In the immediate fasting state, blood glucose is maintained either by glucose released from the breakdown of glycogen (glycogenolysis) or by newly synthesized glucose (gluconeogenesis).

• Glycogenesis: formation of glycogen when blood glucose levels are high to allow excess glucose to be stored in liver and muscle cells.

Glucose homeostasis and the maintenance of blood sugar levels is a major function of the liver.

Ketogenic diet

• Used to treat refractory epilepsy (hasn’t responded to usual treatments) in children (we don’t know the mechanism of action, how it works and the long term implications)
  • Approximately 50% of children on the diet experience a reduction in seizures by 50%
  • Approximately 30% of children on the diet experience a reduction in seizures by 90%
• High fat, adequate-protein, very low carb
• Liver converts fat into fatty acids and ketones
• Ketones used by brain as an alternative fuel source
• Acetone production is a symptom of ketosis
• ‘Classic’ diet has a 4:1 ratio of fat to protein/carbs
• We need 50-60g CHO to maintain brain function.

Lipid metabolism

• Lipogenesis
  • Lipogenesis is the process by which acetyl‐CoA is converted to fatty acids. Subsequent triglyceride synthesis allows energy storage as fat.
• Fats are insoluble in water and are transported in the plasma as protein–lipid complexes (lipoproteins).
• The liver has a major role in the metabolism of lipoproteins. It synthesizes (VLDL – very low-density lipoprotein) and (HDL – high-density lipoprotein) cholesterol.
• Hepatic lipase removes triglyceride from (IDL – intermediate density lipoprotein) to produce (LDL) which is degraded by the liver after uptake by specific cell receptors.
  • IDL only really exists temparily in a tansition period to LDL
• Excess fats or CHO are stored as lipoproteins or triglycerides in the liver.

Cholesterol synthesis: Oxidation of FFA occurs in the liver, depending on the availability of dietary fat. Cholesterol may be of dietary origin but most CHOL is synthesized indogeniously from acetyl‐CoA mainly in the liver, adrenal cortex and skin.

Detoxification

• Liver serves as a gatekeeper between the circulation and absorbed substances
• First pass: every substance absorbed in GI tract passes through liver because blood coming from GI tract goes to liver first.
  • If it didn’t then toxics would permeate the body unhindered.
• Detoxification includes drugs and poisons, and metabolic products such as ammonia, alcohol, and bilirubin via Cytochrome P450 enzymes which are very useful in that they can react and bind to a wide variety of substrates/molecules instead of just one.

3 Detoxification mechanisms

Because many toxins are fat soluble it means they only dissolve in a fatty/oily environment. Once they get to the liver the liver needs to convert them to water-soluble substances so they can be excreted.

• Binding of material reversibly to inactivate it
• Chemically modify compound for excretion
  • 1st Phase: Oxidation whch neutralises the toxin or prepares it to be changed into a different form
  • 2nd Phase: Conjugation: Modification in toxin to something not harmful or less harmful.
    • Less Harmful Conjugation: E.G. Ammonia to urea because urea is still toxic but much less so than ammonia.
• Drug metabolizer for detox of drugs and poisons

Liver Cirrhosis: Chronic Liver Disease

Lifetime of drinking vs not.

• Chronic liver disease resulting from necrosis (dying) of hepatocytes (liver cell) followed by fibrous tissue (scar tissue) deposition with loss of hepatic architecture
  • Livers fibrous tissue changes the structure of the liver and the lose of hepatic architecture (structure) reduces liver function.
• This derangement eventually produces portal hypertension and worsening liver cell failure.

Aetiology (Cause)

• Alcohol is now the most common cause in the West, but viral infection is the most common cause world wide.
• Other common causes: Hepatitis B, Hepatitis C
• Less common causes: Wilson’s Disease & Cystic Fibrosis

Pathogenesis

• Long standing injury to the liver leads to inflammation, necrosis and eventually fibrosis (initiated by activation of stellate cells).
• The liver injury (eg alcohol abuse) stimulate a release of  cytokines which stimulate an excessive release and deposition of collagen fibres (which causes scar tissue) leading to loss of hepatic architecture.

Metabolism of Alcohol

• Alcohol is water-soluble toxin that diffuses into all cells and cannot be stored
• 5‐10% excreted in it’s un‐metabolised form in breath, urine & sweat which means we have 90-95% that the liver needs to metabolise

Alcohol dehydrogenase (ADH)

• ADH is an enzyme that cleaves off hydrogens which allows NAD (co-enzyme) to be converted to NADH
• Oxidation reaction gives off hydrogen
• Accepted by electron acceptor
• NAD to NADH
• Product = (Acetaldehyde) is toxic but this is further converted to acetic acid by acetaldehyde dehydrogenase which takes away another H+ and gets converted finally to Acetyl-CoA. Resulting in CO2 and H20 via the citric acid cycle.

Ethanol (ETOH) = alcohol

Asian populations are known to have a reduced ability to produce alcohol dehydrogenase that can cause red flushing of the skin.

Around 80% of East Asians carry an allele of the gene coding for the enzyme alcohol dehydrogenase called ADH1B2, which results in the alcohol dehydrogenase enzyme converting alcohol to toxic acetaldehyde more quickly than other gene variants common outside of East Asia.^[5][13] In about 30-50% of East Asians, the rapid accumulation of acetaldehyde is worsened by another gene variant, the mitochondrial ALDH22 allele, which results in a less functional acetaldehyde dehydrogenase enzyme, responsible for the breakdown of acetaldehyde[13]

Microsomal Ethanol Oxidising System (MEOS)

Don’t need to remember.

• Able to regenerate some NAD from conversion of NADPH to NADP
• Inducible system that means it kicks in when the system we have can’t metabolise alcohol consumed due to high quantity
• Increases alcohol tolerance with habitual drinking because this system kicks in more often and frequently. A problem because the more you can tolerate the easier it is to drink more which contributes to liver damage.

Gender Differences

Women

• Lower gastric alcohol dehydrogenase (ADH) (59% of that of men)
• Lower first pass liver uptake (23% of that of men)
• Smaller total blood volume and that results in a
  higher blood alcohol level and a greater risk
  of liver disease.

Alcohol Intoxication

Ethanol passes into the brain via the BBB, affecting 3 major areas:

• Forebrain (frontal lobe) ‐ judgement and reasoning
• Midbrain ‐ muscular control and coordination
• Hindbrain ‐Respiration and heart rate

Elimination of Alcohol

• The liver oxidises ~90-95% of the alcohol introduced  into the bloodstream
• The rest via sweat, urine, and breath
• Alcohol is a volatile (evaporates easily)
• Blood vessels in the lungs terminate in networks of capillaries in the walls of the alveoli therefore alcohol is transferred from the blood into the breath
• Alveolar breath contains 1/2100th as much alcohol as there is in the blood but that is how blood alcohol concentration is deduced

Formula for calculating standard drinks:

The number of standard drinks = [Volume of container (l)] X [% alcohol by volume (ml/100ml)] X 0.789

E.G. 0.375 x 4.9 x 0.789 = 1.44 standard drinks

0.789 = specific gravity of alcohol (measuring density of a substance relative to water on it’s ability to float) i.e. <1 = float and alcohol floats.

Blood Alcohol Concentration

• Drink driving legislation is based on blood alcohol concentration (BAC). This is a measure of the amount of alcohol in the blood
• A BAC of 0.05 means that in every 100ml of  blood there is 0.05 grams of alcohol

Rate of Alcohol Removal

Purple Line: Rapid succession drinking one after the next within 30 minutes

Green Line: Spacing out drinks over 4-5h

• Quicker ingestion of alcohol results in a faster
  reduction of blood alcohol content compared to spacing it out over many hours.
• Inferring that it would be smarter from the perspective of being sober quicker to get drunk as quickly as possible compared to spacing out your drinks

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The Pancreas

Week 3

Gland with both exocrine and endocrine functions

Exocrine: secretion from a gland through a duct onto an epithelium (e.g. salivary duct in mouth)

• The exocrine portion secretes enzymes (acinar cells) and (duct cells) into the pancreatic ducts.

Endocrine: secretion directly into bloodstream

• The endocrine portion secretes insulin, glucagon, and other hormones into the blood.

15‐25 cm & 60‐100 g

Four parts:

• Head
• Neck
• Body
• Tail

• Lies posterior to stomach
• Is wrapped in a thin, connective tissue capsule
• Main duct (Wirsung) runs entire length of pancreas

Blood Flow

• The pancreas receives nutrient-rich blood flow from the SI via the portal venous system which triggers hormones such as insulin and glucagon to release.
• Those hormones in the blood get delivered to the liver and because they go straight to the liver the effects the hormones have on the liver are 4x greater than what you will see in the rest of the body.

Functions of the Pancreas

Endocrine cells:

Secrete insulin and glucagon into bloodstream via pancreatic islets cells (make up 1% of cells of pancreas)

Exocrine cells:

Made up of acinar cells and epithelial cells of duct system secrete pancreatic juice (99% of cells of pancreas)

The pancreas houses two distinctly different tissues:

• Exocrine tissue associated ducts
• Throughout the exocrine tissue are several hundred thousand clusters of endocrine cells

The Exocrine Pancreas

The exocrine pancreas secretes enzymes for the breakdown of carbohydrates, lipids and proteins. These enzymes are excreted into the duodenum. There are carbohydrases, which breakdown carbohydrates, lipases, which breakdown lipids, nucleases, which breakdown nucleic acids and proteolytic enzymes, of which there are two types – proteases which breakdown large proteins and peptidases which break small peptides into amino acids.

• The exocrine portion of the pancreas secretes HCO3 and a number of digestive enzymes into the duodenum.
• The enzymes are secreted from lobules called acini (meaning grape or berry) at the end of the pancreatic duct system; the cells are thus referred to as acinar cells.

Pancreatic Enzymes

1. Pancreatic alpha‐amylase

• Which is a carbohydrase
• Breaks down starches (carbs)
• Similar to salivary amylase

2. Pancreatic lipase

• Breaks down complex lipids
• Releases products such as fatty acids that are easily absorbed

A reminder from last week

3. Nucleases

Breaks down nucleic acids (The term nucleic acid is the overall name for DNA and RNA)

Proteolytic enzymes (protease, proteinase, or peptidase)

Any of a group of enzymes that break the long chainlike molecules of proteins into shorter fragments (peptides) and eventually into their components, amino acids.

• Proteases break large protein complexes into peptides…
• Then Peptidases break small peptides into amino acids
• 70% of all pancreatic enzyme production is related to enzymes that break down proteins.
  • Secreted as inactive proenzymes
  • Activated after reaching small intestine

If pancreatic enzyme production related to proteases falls by 10%~ we can end up with malabsorption of proteins.

The exocrine portion secretes enzymes (acinar cells) and (duct cells) into the pancreatic ducts.

The endocrine portion secretes insulin, glucagon, and other hormones into the blood.

Pancreatic pH buffering

Secretin stimulates bicarbonate (HCO3‐) secretion in the pancreatic ducts when S cells detect that acid is present in the duodenum.

Important for maintaining structural integrity/lining of gut.

• HCO3 is secreted by the epithelial cells lining the pancreatic ducts. The high acidity of the chyme coming from the stomach would inactivate the pancreatic enzymes in the small intestine if the acid were not neutralized by the in the pancreatic fluid.

Action of Pancreatic Enzymes

Enzymes secreted by the pancreas digest fat, polysaccharides, proteins, and nucleic acidsto fatty acids and monoglycerides, sugars, amino acids, and nucleotides.

Pancreatic Enzyme Deficiency

Most common causes are:

• Chronic pancreatitis (chronic inflammation of the pancreas leading to enzyme release dysfunction)
• Cystic Fibrosis (recessive hereditary disease affecting primarily caucasian populations)

Cystic Fibrosis (CF)

• Present at birth
• Diagnosed using heel‐prick blood test
  • If positive a sweat test to confirm amount of chloride and NA
• Prognosis?? Changed a lot over the decades with people living longer now into their 30s.

Physiological issues

• Lung disease (possibly lung transplant)
• Pancreatic Insufficiency (PI)
• Malabsorption
• CF related diabetes
• Other GI tract symptoms

Pancreatic Insufficiency

• Causes Mal‐digestion and malabsorption Ion transport is defective (Cl‐ & HCO3‐)
• Lower level of digestive enzymes
• Pancreatic fibrosis (scarring)
• Results in malabsorption, steatorrhoea and fat soluble vitamin deficiency

Treatment

• Enzyme replacement therapy via digestive enzyme capsules
• Administered at meals containing protein +/‐ fat
• Not needed for foods/meals with little or no fat
• Strength of capsule varies

Dietary Treatment

• Similar to the healthy population with some distinct differences
• Choose a nutritious, high energy diet from a wide variety of foods because of the 50%~ increase in BMR compared to the average for people with CF.
• Eat plenty of fat & sugar
• Eat more breads, cereals, meats, protein foods and milk products
• Use plenty of salt

The Endocrine Pancreas

• The endocrine portion of the pancreas takes the form of many small clusters of cells called islets of Langerhans
• Pancreatic islets house three major cell types, each of which produces a different endocrine product: Alpha, Beta & Delta cells

Alpha cells (A cells) secrete the hormone glucagon

• We don’t know as well how glucagon is released from a cells. All we know is amino acids trigger glucagon.

Beta cells (B cells) produce insulin and are the most abundant of the islet cells.

• Insulin leaves the beta cells via GLUT 2 transporter and this allows glucose to enter into the beta-cell. Then processes like glycolysis are undergone or it is broken down into components that are sent through the krebs cycle to produce ATP.

Delta cells (D cells) secrete the hormone somatostatin which is also produced by a number of other endocrine cells in the body

Pancreatic Hormones Regulate Metabolism

Structure of Insulin

Insulin is protein/hormone, composed of two chains held together by disulfide bonds

Proinsulin consists of three domains:

• an amino‐terminal B chain
• a carboxy‐terminal A chain
• a connecting peptide in the middle known as the C peptide

Functions of Insulin

Remember: Exam

Targets of Insulin action

Carbohydrates

• Increased activity of glucose transporters
• Activation of glycogen synthase that converts glucose to glycogen
• Inhibition of phosphoenolpyruvate carboxykinase (PEPCK) which inhibits gluconeogenesis 

Lipids

• Activation of acetyl CoA carboxylase
• Activation of lipoprotein lipase which increases breakdown of triglycerides 

Insulin release

• The normal fasting blood glucose concentration in humans is 80 to 90 mg per 100 ml, associated with very low levels of insulin secretion.
• Almost immediately after meals, plasma insulin levels increase dramatically.
• Elevated glucose not only stimulates insulin secretion, but also insulin synthesis
• A key trigger for the release of insulin after a mixed meal is glucose entry into pancreatic beta-cells

Insulin Release Over Time

Insulin Control Loop

Eventually, plasma glucose decreases which operates on a negative feedback loop on beta cells so less insulin is progressively secreted and plasma glucose reaches homeostasis.

Insulin & Diabetes

Type 1 

Caused by insufficient insulin as a result of the destruction of beta cells

Type 2

Develops over time causing insulin resistance as pancreas produces more and more insulin to do the same job which eventually results in chronic high insulin secretion and plasma glucose

Others include

• Gestational diabetes
• LADA (Latent Autoimmune Diabetes of Adults) – T1 diabates that occurs in adulthood

Type I Diabetes Mellitus

• β cells of the islets of Langerhans are destroyed by autoimmune attack which may be provoked by environmental agent (e.g. virus)
• Glucose cannot enter cells (as there is no insulin) or there is a decreased amount of insulin where glucose can’t enter the cell = decreased glucose utlisation
• Rate of fat synthesis lags behind the rate of lipolysis which means fatty acids are converted to ketone bodies, resulting in ketoacidosis
  • ketoacidosis = high production of ketones where it increases the acidity of the blood
• Increased blood glucagon concentration because beta cells can’t produce enough insulin to shuttle glucose into the cell, so because insulin is low glucogen is produced which acts to increase blood glucose further!
• Stimulates glycogenolysis in liver

Consequences of Uncorrected Insulin Deficiency in Type I Diabetes

Osmotic diuresis causes a loss of minerals through constant frequent urination. A common symptom of diabetes is frequent urination.

Glucagon

• Peptide hormone consisting of 29 amino acids
• Acts on the liver to cause the breakdown of glycogen
• Inhibits glycolysis (converts glucose into pyruvate and H+)
  • How much of the inhibition of glycolysis would contribute to decreased time to fatigue because less H+ and pyruvate are being circulated during fasted exercise? = It’s possible yes, but well outside the scope of this unit (and the area of specialisation of the Unit Chair).
• Increases production of glucose from amino acids
• Increases lipolysis
• This results in the maintenance of blood glucose levels during fasting

The action of Glucagon

• Glucagon prevents hypoglycemia by IN cell production of glucose
• Liver is primary target to maintain blood glucose levels

Targets of Glucagon action

• Activates a phosphorylase which cleaves a glucose and phosphate off glycogen and that allows the production of glucose.
• Inactivates glycogen synthase (converts glucose to glycogen) resulting in less glycogen synthesis
• Increases phosphoenolpyruvate carboxykinase (PEPCK) which stimulates gluconeogenesis
• Activates lipases that allow triglycerides to be broken down
• Inhibits acetyl CoA carboxylase which decreases FFA formation
• This results in more production of glucose and substrates for metabolism

Regulation of Glucagon Release

• Increased blood glucose levels inhibit glucagon release
• Amino acids stimulate glucagon release
  • Consider that in relation to a high PRO low CHO diet
• Stress: epinephrine acts on beta‐adrenergic receptors on alpha cells which increases glucagon release
• Importantly insulin inhibits glucagon secretion

Glucagon Control Loop

Effect of Feeding and Fasting on Metabolism

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Carbohydrates

Week 4

Monosaccharides (Hexoses)

= one CHO unit / one saccharide molecule

C₆H₁₂O₆ = CHO. 

Glucose

• principle monosaccharide (account for 90%~ of CHO intake)
• 6 carbon (hexose) ‐ sole component of starch and glycogen
• Starches and glycogen are made up of many units of glucose

Fructose

• 5-7% of fructose
• sweetest monosaccharide
• Fruit, honey and corn‐syrup
• Some countries will use fructose to sweeten their drinks like coca-cola whilst Australis uses sucrose which is why overseas coca-cola tasted sweeter

Galactose

• A milk sugar found as part of lactose in dairy products

Structure of Hexoses (Monosaccharides)

• Contain 6 carbons hence the name hexoses
• The C, H & O provide the scaffolding of the chemical structure
• Galatose and fructose are broken down into glucose to be utlised

Disaccharides

• = two CHO monosaccharides units joined together by a glycosidic bond
• varying combinations of monosaccharide molecule’s join together to form various disaccharide
• Water-soluble which means they can dissolve

Glycosidic bonds

• Disaccharides form via joining two monosaccharides through a condensation reaction.
• This reaction creates a glycosidic bond which is a bond between two monosaccharides to form a disaccharide.
• Two types of glucosidic bonds:
  • alpha α) bonds CAN be digested to be utilised
  • beta (β) bonds are RARELY digested
    • Found mainly in dietary fibre and feed the bacteria in the LI – we get fermentation of the fibre which produces gas.
    • Lactose, IF we don’t have lactase or you are lactase deficient.

Maltose

• glucose + glucose
• fermentation intermediate Sucrose

Sucrose

• fructose + glucose
• Most common disaccharide in the Australian diet

Lactose

• galactose + glucose
• milk sugar

Condensation Reaction

• A condensation reaction produces water
• An OH and H combine together to create H20

High Fructose Corn Syrup

• HFCS is rarely used in Australia (common in USA), compared to cane sugar, whcih is cheaper and more readily available. The truth is HFCS and cane sugar is the same thing – they both contain fructose and glucose. Cane sugar is 50 per cent glucose and 50 per cent fructose. High-fructose corn syrup is about 55 per cent fructose and 45 per cent glucose.
• History: In the 1970s the US started subsidising corn production. There was a very high supply and not enough demand to me it. They found out they could use it as a substitute for table sugar (sucrose) and they broke down the startch in the corn to free glucose + fructose.
• https://corn.org/products/sweeteners/

Significance of glycosidic bond

Lactose Intolerance

• Associated with a deficiency of intestinal lactase (β galactosidase).
  • β = its going to break a beta bond
  • galactosidase = breaks down lactose into galactose and glucose
• Worsens with advancing age
• Ultimately affects 60‐90% in some ethnic groups
• Primary lactose intolerance: had from birth
• Secondary lactose interference: developed from lifestyle and dietary factors
• Symptoms: abdominal pain, flatulence, frothy diarrhoea.
  • Why? When we compare beta-bonds lactose is a much simpler sugar as a disaccharide compared to dietary fibre (polysaccharide). So the intestinal bacteria in the LI bacteria feed off these simpler sugars and produce gases like methane and hydrogen that cause gassiness. 

Lactase Persistence 

• Routine consistent exposure to lactose can create lactase persistence in some population which continues that adequate release of lactase.
• Taking long bouts of non-lactose or minimal lactose consumption and then large acute bouts of lactose can flare up lactose intolerance symptoms because the body doesn’t have enough of the enzyme to break down the large amount.

This just includes primary lactase deficiency, so relative % of total population who have problems digesting lactose is going to be higher because of secondary induced lactose intolerance.

Oligosaccharides

Oligo = many

• 3‐8 monosaccharides joined together
• Can be used as sweeteners without being too sweet
• Generally synthesised in labs
• Most of the few naturally occurring oligosaccharides are found in plants.
• Chains of fructose joined by beta bonds which means vast majority of them aren’t digested

Polydextrose, Maltodextran (α‐glucan)

• glucose polymers (large molecules joint together)
• variable digestibility
• A single free glucose molecule attracts water and a chain of glucose molecules has the same osmotic attraction which is why sports drinks hydrate and deliver energy faster because you can absorb from your stomach into your SI more glucose than if you had sugar (free glucose) alone. If it was just free glucose we’d be more likely to overload our gut with free glucose and that osmotic effect would draw more water into the gut causing it to be passed through urine. By using oligosaccharides like polydextrose because they’re not free glucoses they work better for us from a hydration perspective.
• Contained in sports drinks

Raffinose, Stachyose

• Variable numbers of glucose and fructose
• Foods‐ beans, peas

Inulin

• fructose polymers
• derivatives used as sweeteners
• key term ‐ hetero‐oligosaccharide or mono‐oligosaccharide

Oligosaccharides – cell function

Blood Antigens

• Most oligosaccharides occur in the body after post-translational modification which is what happens when we add protein to glucose.
• Oligosaccharides are important in cell signalling
• Blood antigens tell us if/when/how fast you clot which is determined by chains of CHO that are stuck on the outside of the RBC. Because antibodies bind to the hexoses it triggers the blood clotting response. 
• This is mentioned to demonstrate that CHO have many more functions than just providing energy but they play a role in things like blood clotting.

‘Simple’ vs ‘Complex’ Carbohydrates

Not formal definitions just a way to differentiate for the lay community 

• Simple CHO = Monosaccharides and disaccharides
  • You’ll recall that monosaccharides are single carbohydrate units whilst disaccharides are two monosaccharides joined together by a glycosidic bond
• Complex CHO = generally greater than 10 monosaccharides
  • starch and non‐starch polysaccharides

Polysaccharides

3 Types: Starch, Glycogen and Cellulose. 

• Poly = many
• 8+ glucose molecules stuck together = polysaccharide joined by alpha bonds
• Must be broken down into monosaccharides to be utilised

Starch (α‐glucans)

• 80‐90% of all polysaccharide eaten
• Many glucose’ joined together via alpha bonds, therefore, making it digestible.
• Carbohydrate storage of plants
• We cook starch with water because the a-glucans are tightly formed together and the water causes them to expand to get water in there to make the starch more easily digestible so we can harness the glucose for energy.
• The GI index describes the rate at which one digests startches.
• Starches that have been liberated from granules in food during cooking is said to have been gelatinished

Two Types of Starch Molecules/Granules:

These two types are the major determinints behind the rate of digestion/GI of starch.

1. Amylose (Slow & Lo)

• Slow rate of digestion (low GI) because it’s a long chain of glucose packed tightly together
• 15‐20% of starch granules
• Straight chain (1,4‐ α bonds)
• The relative content of amylose determines how long it takes to cook a starchy food like rice.

2. Amylopectin (Fast & High)

• Branched chains (1,4;1,6 ‐ α bonds) which means it can cook faster we can digest it faster (high GI)

Human storage form ‐ Glycogen

Starch Polymers: Amylose

Long and straight with a tight ring.

Starch Polymers: Amylopectin

Branches off.

α‐Glucan (Starch) Digestion: From Polysaccharide to Monosaccharide

1. Starch digestion begins in the mouth with the release of salivary amylase. This starts to breakdown starches into small polysaccharides
2. Once food enters the stomach, the acids there inactivate the saliavary enzymes.
3. When chyme enters the small intestine, the pancreas releases pancreatic amylase which continues starch digestion.
4. In the small intestine, on the surface of intestinal cells, are disaccharide enzymes. These hydrolyse (breakdown) disaccharides into monosaccharides.
   • Maltose becomes two glucose units, sucrose becomes fructose and glucose, and lactose becomes galactose and glucose.
5. These monosaccharides are then absorbed by the intestinal cells.

• Salivary α ‐amylase early digestion
• Pancreatic α‐amylases do most of the job breaking down a-bonds of starches from polysaccharides to oligosaccharides
• No specificity for α ‐(1,6) branches
• Poor specificity for small oligosaccharides
• Membrane Surface Oligosaccharidases are hanging on to enterocytes that line the villi of the SI.
• Large protein complexes secreted from enterocytes to brush border in order to remove single glucose units

 

Glucose Absorption Video https://video.deakin.edu.au/media/t/1_tac7ibae

The process of absorption of these monosaccharides is called facilitated active transport.

Facilitated because it requires NA

Active because the concentration of glucose is higher in the cells than in the gut

• The transport of glucose into the cell uses a protein known as SGLT1.
• The binding of NA to the transporter changes the shape of the transporter to allow glucose to bind to it more effectively.
• When the binding sites of SGLT-1 are open to the gut the high NA concentration makes binding of NA into the transporter highly probable.
• This allows a more efficient binding of glucose to the transporter.
• Once NA is in the cell it is transported out of the cell via the NA-K ATPase pump.
• Once glucose goes through the facilitated transport mechanism there is a pore on the other side of the cell that allows glucose to travel to the bloodstream.

 

• There are specific pores/transport proteins in the SI cells that allow you to absorb glucose into your blood stream. That requires a facilitated glucose transporter (e.g. GLUT-2), because glucose disolves in water and cell membranes are composed of fat, so you need a protein to make a hole to allow transport through.
• It’s ‘active’ because you pump NA out of the cell to get glucose into your body. The NA wants to get from a high concentration in the intestinal lumen to a lower concentration in the intestinal cell because it doesn’t like there being a difference in concentrations.
• Summary: NA gets pushed out of the cell so it can get back into the cell and bring glucose with it. The advantage of this is that it doesn’t matter how many molecules of glucose are left – you can get every single last one of them from the lumen into your cells.
• Your body spends 40%~ of its ATP (over a day) pumping NA out of the cell through the NA-K ATPase pump.

Fructose absorption is performed by facilitated transport (not active) because the body hasn’t seen it historically as a large source of dietary energy (could be a clue into % of dietary fructose (fruit) we ate historically as we evolved). Thus fructose absorption is slower because it’s only facilitated.

Fructose Malabsorption/Intolerance 

Because fructose is absorbed slower and has an osmotic effect, meaning it can attract high loads of water into the intestine. The body tries to flush these high concentrations of fructose LI by adding more fluid so then it’s excreted. Some people are sensitive to this and it causes a variety of GI issues like diarrhea.

Why/How? There is a dysfunction with the intestinal transporter and some people just have a bigger osmotic effect when they consume fructose we don’t know exactly why.

Toddler Diarrhea

Commonly occurs when children are given high amounts of fruit or fruit juice and this high fructose load creates a high osmotic load drawing all this water into the LI causing diarrhea.

Glucose Transporters

Each glucose transporter delivers glucose to different sites.

GLUT1 ‐ Erythrocyte, blood‐brain barrier, placenta, fetal tissue
GLUT2 ‐ Liver, pancreas beta‐cells, kidney, small intestine
GLUT3 ‐ Brain
GLUT4 ‐ Skeletal muscle, heart, adipocytes (GLUT4 is the most insulin-responsive transporter)
GLUT5 ‐ Small intestine
GLUT7 ‐ Endoplasmic reticulum of hepatocytes

Glucose: What happens after a Meal?

• Meals supply between 50‐150 g new glucose
• Free glucose content of the body is 15‐25 g of which only 5g is in the blood (keeping our blood glucose stable around 3‐5.5 mmol/l)
• A reminder that blood glucose concentration carefully
  controlled by:
  • Insulin (pancreatic β‐cells)
  • Glucagon (pancreatic α‐cells)

Remember insulin is indiscriminate anabolic hormone it causes storage of fat, PRO and glucose.

Actions of Insulin On Glucose

1. Glucose Transport

• Insulin activates the transport of GLUT4‐containing vesicles to the cell surface TO major tissues like skeletal muscle, adipose tissue.
• GLUT 4 is the most insulin-responsive of the GLUT transporters.
• The exact mechanisms of this coupling are unknown

2. Intracellular Glucose Metabolism

How consuming glucose promotes the use of glucose? 

Glucose promotes it’s own oxidation. When we eat CHO we see glycolysis – glucose being converted to pyruvate via glycolysis and the pyruvate being converted to acetyl-CoA (pyruvate dehydrogenase pulls H off pyruvate to create acetyl-CoA). That enzyme is really sensitive to insulin so when you have high levels of glucose and insulin we see an increased conversation of pyruvate to acetyl-CoA so you metabolise more glucose.

Glycogen Synthesis

Insulin activates glycogen synthesis via Glycogen synthase

Why we see acute weight loss with fasting/low carb:

Every gram of glucose in glycogen is bound with 3~ grams of water so 500-600 grams of stored glyocgen in the muscle/liver can weigh 1.5-.1.8kg.

Liver

• 120g (8% of mass)
• Maintain blood glucose concentrations

Muscle

• 300‐500g (2% of muscle mass)
• Energy store
• Glycogen storage limited

Glycogen molecules are very large

3g water/g glycogen

294.2kJ/g

Size of Carbohydrate Stores & Energy It Provides

Practical Implication = how much stored glycogen do I have to expend during exercise and how long will it last.

If your body has 1900~ cals (8000kj) of stored glycogen/circulating glucose you may exhaust that fully in 2-4h of running *though keep into consideration fatty acids and amino acids are used to an extend as well it’s not a all-or-nothing approach.

3. Liver Glucose Output

• Liver receives high concentrations of insulin
• The response = inhibition of glycogen breakdown (glycogenolysis) inhibition of glucose creation (gluconeogenesis)
• Results in reduced liver glucose output

What Happens If I Eat Too Much Carbs?

Turning Carbohydrates to Fat: de‐novo lipogenesis:

• To get CHO to turn to fat takes a very large amount of CHO.
• DNL converts excess carbohydrate into fatty acids (technically glycerol – an alcohol) that are then esterified to storage triacylglycerols
  • The production of glycerol allows FFA’s to combine with it to form a triacylglyde which is the storage form of fat.
• Overfeeding Group: 150-200% of energy needs. Even with this huge amount of overfeeding we only saw a 9% increase. So the amount of CHO contributing to DNL is only 13% even though our caloric intake is double~ what we need to maintain our weight. To counter the overfeeding what our body does is increase glucose oxidation – so more glucose ingested caused much more glucose oxidation. 
• It’s not that you turned all that excess glucose into fat (it’s pretty minor actually). Instead, you’ve turned up your glucose use (oxidation) but the downside of this is your not using as much fat for fuel so the fat you costume in your diet is more likely to be stored immediately. 
• A justification for the classic bodybuilding high CHO low fat because of more glucose = more glucose oxidation and storage with minimal fat storage. Whereas if you keep fat and carb high in a surplus you will store more fat.

Resistant Starch

Resistant starch is a carbohydrate that resists digestion in the small intestine and ferments in the large intestine. As the fibers ferment they act as a prebiotic and feed the good bacteria in the gut. E.G. Green bananas, sweet potato, lentils.

• RS1 ‐ physically trapped starch; i.e. trapped in whole
  grains
• RS2 ‐ resistant starch granules; compact starch granules which hydrate slowly (high in amylose – slow and low)
• RS3 ‐ Retrograded starch; starch that has been allowed to cool and recrystallise like cooled pasta after heating.

Ability to manufacture white bread high in fibre

Estimates of RS vary from 5 to 40 grams daily

Definitions of Dietary Fibre

Physiological Definition

Dietary fibre is defined as; “Plant material that resists digestion by human alimentary enzymes”

Problem with that definition = to determine health benefits need to know chemical constituents are.

Chemical Definition

“non‐starch polysaccharides plus lignin”

Problem = taking isolated constituents does not replicate the
actions of the whole food

Dietary fibres resist digestion in the SI therefore they’re called resistant starch. 

Non‐Starch Polysaccharides (non α‐glucans)

Mostly cellulose ‐ 80‐90% in plant cell walls and water-insoluble because they’re b-glucans

Cellulose (major dietary fiber)

• Many glucose’ joined together via beta bonds therefore making it indigestible fibre.
• β(1‐4 and 1‐3) glucan ‐ 30% of raw vegetables is cellulose
• Really tight strands so bacteria in gut can’t digest

Hemicellulose

• β ‐linked mixed monosaccharides
• xylan, galactan, mannan
• Component of cell wall gets broken by chewing
• More soluble and digestible by intestinal bacteria compared to cellulose

β‐glucan (cellulose)

Non‐Starch Polysaccharides

Pectins

• Dissolve and swell when placed in water (water soluble)
• Glues cells together
• Mixed β‐linked polysaccharides
• *make jams thick

Gums & Mucilages

• Gums‐secreted from an injury site of a plant
• *Commonly used as thickeners for palatability
• gum Arabic
• Mucilages ‐present in cells, to hold water
• Example ‐ guar gum

Non‐Carbohydrate Component

Sometimes referred to as anti-nutrients because can bind to nutrients and pass into the LI instead of getting absorbed.

Lignin

• Highly complex chemical
• Not usually important in human nutrition
• High in seed coating

Phytates and Tannins

Have the capacity to bind to positively charged ions and
reduce mineral absorption

Soluble & Insoluble Fiber

a) apple

Why Is Fiber Important?

Physical Properties of Dietary Fibre

Viscosity

Pectins and gums are able to form thick solutions which are satiating and filling. A good tool to curb overeating.

Water‐holding capacity

Ability to retain water within a matrix which adds to stool bulk.

Susceptibility to Fermentation

Many NSP and all RS may be fermented by the bacteria in the large intestine

Binding capacity

Depending on the charge of the polysaccharide, some are able to bind to lipids, bile acids and minerals.

Physiological Responses Related to Health

Stomach and Small Intestine

Viscosity

• Pectins and gums able to form thick gels
• Delay the rate of gastric emptying
• Delay digestion and absorption of nutrients in the small intestine

Physiological Responses Related to Health

Large Intestine

Fibre reaches the LI largely intact. It is here that digest fibre, creating short-chain fatty acids and gas.

Susceptibility to Fermentation

• Fermentation by microorganisms results in the formation of endproducts that influence large intestinal physiology
• Short-chain fatty acids (butyrate) important for gut health
• Reduced pH
• Gases ‐ methane and hydrogen

Binding Capacity

Fibre can bind to cholesterol, bile acids and some minerals for excretion in the large intestine

Water‐holding Capacity

Reduced transit time, increased stool weight, frequency and dilution of bowel contents

• “Fermentation in the LI is quite healthy and useful.”
• CHO get broke down into pyruvate which get broken down into anti-carcinogenic compounds (those 3 acids).

Dietary Fibre & Cancer Risk

Colorectal cancer goes down as fiber intake increases. Even at 50g-60g OR still = <1.00.

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Proteins

Week 5

Proteins & Amino Acids

Almost every cell in the body is made up of PRO

Structure and function of every protein in the body is determined by:

1. the amino acid composition
2. number and order of linkages
3. folding of amino acids into protein
4. interactions with other chemical groups (i.e. glucose, phosphate)

Amino acids

• Are the building blocks of PRO
• Used by all tissues
• The biological value of a food protein is a measure of how closely the amino acid distribution in the food meets the amino acid needs of body tissue
• After getting processed by the gut they are send to the liver in the blood where the liver distributes to various tissues around the body
• There are two main groups of amino acids: essential and non-essential.  An amino acid ‘subgroup’ does exist though – that of conditionally essential amino acids.
• ‘Vast majority of amino acids consumed aren’t incorporated into muscle proteins at all… even under periods of rapid growth, under 5% of amino acids specifically deposited into muscle is used from meals. As we move from intermediate to advanced that % can drop to as low as 1%” – Layne Norton

Each amino acid contains an acid group (hence the name amino acid) and a side group. It’s the side group that distinguishes each of the 20 different amino acids.

• An amino (amine) group
• A carboxyl group
• An R (variable) group, which distinguishes each of the 20 different amino acids and dictates structure and function of the amino acid

*everything comes off a central C molecule 

4 Examples of Various Chemical Structures of Amino Acids

This show’s how different the side groups can be.

Each amino acid has unique properties

Hydrophillic will dissolve in water.

The 20 Amino Acids

• All amino acids are metabolically necessary and technically essential. Where we distinguish EAA’s vs NEAA’s is their presence in food or not.
• Almost every PRO we make uses all 20 AA’s so if we are deficient in one protein synthesis suffers
• BCAA’s get into the blood stream quicker to be utilised.

Essential (Indispensable) Amino Acids

• EAA’s: Your body can’t produce them at all or fast enough for our requirements.
• 9 amino acids have carbon skeletons and cannot be synthesised at a rate sufficient for requirements
• Thus must be present in the diet

Non‐Essential (Dispensible) Amino Acids

• Don’t need to necessarily source from food
• Can be synthesised and changed in the liver
  • This is the process of passing one amino group from one amino acid to a carbon backbone is termed transamination AKA pulling the AA apart and swapping side chains – the process where the body can make non-essential amino acids

Conditionally Essential Amino Acids (CEAA)

A conditionally essential amino acid is dependent upon a precurser.

The human body can make the required side chain but to do so requires an different side chain. An example of this is the amino acid phenylalanine. Phenylalanine provides parts of the side chain required for synthesis of tyrosine. This makes phenylalanine a conditionally essential amino acid.

May be conditionally essential for a disease state or a stage of life (growth and development)

• 1. CEAA synthesis is dependent on availability of single precursor e.g. tyrosine (NEAA) is synthesised from phenylalanine (EAA) in the liver
• Phenylketonurea (PKU) is an impairment in the enzyme responsible for this reaction that allows tyrosine to be synthesised from phenylalanine
  • Phenylalanine can increase to toxic levels in the bloodstream leading to neurological damage. People with PKU need to eat foods low in phenylalanine.

• 2. Rate‐limiting at particular stages of development or during disease states
  • Infants need a relative very high amount of PRO to sustain rapid rate of growth
  • e.g. premature babies (30W~) cannot synthesise cysteine, proline and glycine sufficiently to meet demands for development so breast milk is often supplemented that contains those AA’s.

More about Amino Acids

• Some amino acids are glucogenic = they can be made into glucose
• Some amino acids are ketogenic = they can be made into ketones or a‐keto acids

Some are both

• Depending on one’s metabolic need they can be made into glucose or ketones.
• Proteins can’t technically be stored
• 5-10% of AA ingested are used for structure and function, the rest is used for energy.
• Excess PRO ingested get’s exreted as nitrogen in urine. Nitrogen is contained in urea.

Peptide bonds

• When we joint an AA to another AA to make a PRO that occurs through a peptide bond. 
• Dehydration reaction = we lose a water molecule
• 2 AA together = dipeptide
• 3 AA together = tripeptide

Each protein has a unique shape

That shape relates to it’s function

Levels of protein structure ‐ 1

Primary Structure = the sequence of amino acids forming its polypeptide chains (AA in their simplest form repeating themselves over and over again)

Levels of protein structure ‐ 2

Secondary Structure = coiling or folding of the chain, stabilised by hydrogen bonding.

The tight curls of the chain is maintained due to the H bonds.

Levels of protein structure ‐ 3

 

What We Use Protein For In The Body

The wide variety of functions protein is used for is why we have so many different protein structures because structure determines function. 

Proteins

• In the body of a 70kg person, 11‐16kg is protein
• Nearly half of that 11-16kg is in the skeletal muscle, followed by blood and skin

One‐half of the total protein content is in the following proteins:

• collagen (skin/joints)
• myosin/actin (contractile proteins)
• haemoglobin (carries O2)

Examples of half‐life regeneration of proteins

• Red blood cells – every 120 days
• Intestinal mucosal cells ‐< 1 day
• Liver cells – months
• Collagen & myosin heavy chain ‐ approx. 100 days
• Proteins turnover – constant degradation and synthesis

When proteins breakdown the AAs can be:

1. Recycled or
2. Nitrogen removed (urea) and carbon skeleton used as energy

The Dynamic State of Protein Turnover

• Human body is approx. 16% protein
• Proteins are in constant turnover (degradation & resynthesis) – dynamic state
• At any point in time ~3% of total body protein is recycled every day (approx 200g) and this takes a lot of energy to do
• PRO are so important there is a highly efficient recovery process that occurs when we degrade and break down PRO into AA’s.
• Net protein loss may be as low as 2g per day *dietary intake dependent. The more excess PRO you consume the more lost as nitrogen.
• The measure of how quickly proteins turnover is based on its half-life

Nitrogen Balance

A proxy for PRO balance 

Nitrogen can’t be stored it must be excreted

How much and when?

Nitrogen/Protein Balance

• A measure of protein intake: Protein in = Protein out
• Positive: More synthesis than degradation
• Negative: More degradation than synthesis

A woman who is pregnant could be said to be in positive nitrogen balance

Diurnal variation in protein synthesis

But how long does it take to reach negative nitrogen balance post meal?  This graph is lacking that practicality.

Amino Acids Metabolism

• Every cell in the body maintains a pool of AA’s to create PRO they need at any time (note it’s not technically a storage system)
• Excess PRO is broken down into ammonia which is then converted to urea in the liver which is processed by the renal system and excreted

Cellular Responses to Amino Acids

• BCAA’s trigger these intracellular signals to allow MPS to upregulate to a greater extend and rate than non-BCAA’s for the purpose of muscle repair and growth.

Branched Chain Amino Acids

Protein Degradation

Co‐regulation of the degradation/re‐synthesis pathways very important for:

• maintaining cellular function
• regulating growth/wasting
• control of enzyme levels
• Synthesis and degradation are controlled separately

Both influenced by:

• protein intake and energy status inake
• hormones (insulin, growth factors, growth hormone and
  glucocorticoids)

Irrevocable catabolism ‐ losses (~5‐10g/day)

2 possible reasons for degradation

• Amino acid required for the synthesis of new protein (e.g. extended fasting once fat stores diminished)
• Amino acid in excess

Step 1 ‐ Protein cleavage

Breaking down into individual AA’s in the liver.

Step 2 ‐ Nitrogen removal *if AA are in excess 

• Nitrogen removed from the amino acid leaving a carbon skeleton ‐ deamination
• Nitrogen is contained in ammonia which is toxic to cells
• Converted to urea
• Urea excreted by the kidneys

Nitrogen & Carbon Go Separate Ways: How Amino Acids Make Glucose & Urea

Excess AA’s are broken down for energy and/or excreted. 

• [Right]: Carbon skeleton is used for energy via the citric acid cycle – produces by-products and ends up helping create glucose via gluconeogenesis
• [Left]: NH4 (ammonia) converted to urea and exreted

Protein Digestion Summary

1. Once swallowed food reaches the stomach, hydrochloric acid uncoils proteins and activates the stomach enzyme pepsin
2. This enzyme, along with hydrochloric acid creates smaller polypeptides out of the eaten protein.
3. Once in the small intestine pancreatic, and small intestine enzymes known as proteases split the polypeptides further to create tripeptides, dipeptdies and individual amino acids.
4. The next step of protein digestion involves enzymes on the surface of the small intestinal cells hydrolyzing peptides for absorption.
5. It is here that any tri and di-peptides are further broken down to individual amino acids.

Protein Digestion 1

1. Acid Hydrolysis in Stomach

• Acid pH / HCL denatures PRO
• Pepsin breaks large PRO into smaller PRO in the stomach
• (When PRO is in SI) attack internal bonds, cleaving into smaller chain lengths

Denaturation of Proteins

• What can cause denaturation: Heat/acid/alkaline/enzymes
• The result is the alteration of the protein’s three dimensional structure in an acidic environment in the stomach.
  • E.G. Think about what happens when you fry an egg. That is the process of denaturation via heat.

Protein Digestion 2

Summary: Consider the specifics of protein digestion in the small intestine. This is the site of activation and inactivation of enzymes. Enteropeptidase, also known as enterokinase converts pancreatic trypsinogen to trypsin. In turn, trypsin inhibits trypsinogen synthesis. Among other actions, trypsin also converts pancreatic chymotrypsinogen to chymotrypin. There are other various enzymes that are also involved in protein digestion, these are known as intestinal tripeptidases and dipeptidases. These enzymes are are non-specific and eventually break down tri and di-peptides to amino acids.

• When PRO enters the SI the pancreas releases trypsinogen (inactive) which is activated via enteropeptidase into the active trypsin.
• The activation of trypin activates a range of enzymes by the SI/pancreas known as oligopeptidases (means they’re an enzyme breaking down a peptide bond to end up with AA’s)

Facilitated Active Transport

• NA being pumped against the concentration gradient that allows tri/di-peptides/AA’s to be absorbed.
• These are transported across the cell in a facilitated way and then actively transported to the blood stream to the liver

Amino Acid Absorption

These are the end products….

• AAs, Di‐ and tri‐peptides
• Tri‐ are further digested by membrane bound enzymes
• Absorption is governed by active transport which is sodium and energy dependent
• 3 major group‐specific active transport systems: neutral, basic and acidic AAs
• Small intestine plays an important user of AAs
• Most glutamine, almost all glutamate and aspartate
• Between 3‐50% of branched chain AAs

Protein Absorption

Newborns ‐ first 24 hours after birth mothers produce colostrum as breast milk

• Colostrum provides Immunoglobulins which provide protection against bacteria which is critically important for an infant
• This promotes Passive immunity to bacteria that the mother has been exposed to

In Adults

• We absorb some immunoglobulins

Paracellular routes

• Tight junctions between cells

Intracellular routes

• Endocytosis
• Pinocytosis

Protein Regulation after a Meal

• A fraction of total energy supplied by proteins is relatively small
• Careful regulation of protein intake to protein oxidation
• Nitrogen balance

Insulin

• PRO can help make insulin
  • PRO can also trigger an insulin response
• Stimulates amino acid uptake by liver, muscle, kidneys and brain
• Activates gene transcription

 

• Amino acids excess to requirements are transported back to the liver and are deaminated (Oxidised or gluconeogenesis)

Protein Synthesis Following Meals

• In healthy adults, protein consumption on a meal‐to‐meal basis
  stimulates muscle protein synthesis
• Between meals – degradation (oxidation, catabolism)

Coeliac Disease ‐ Gluten

• Gluten relies on gastric and pancreatic enzyme to digest it
• 0/left bottom image = healthy villi / 3-4/bottom right image = flattened damaged villi
• In people with CD gluten escapes digestion and get’s in between the intestinal cells and activates a strong immune response resulting in a destruction and flattening of the villi reducing the surface area of the villi and nutrient absorption capabilities

Where to find gluten

E.G. Soy sauce and foods like it are derived from ingredients that have gluten in them

Protein in Food

Protein in our diet comes from many sources

• need enough essential amino acids for new protein synthesis and non‐essential amino acids to meet the requirements for total synthesis

Need to have a balanced mix of essential amino acids in our dietary protein which reflect the body’s requirements

Protein quality is how effectively a dietary protein meets the essential amino acid requirements of the body

Protein Quality

Complete proteins (animal origin)

• Contain all essential AAs

Incomplete proteins (plant origin)

• Missing some essential AAs
• Requires complimentary foods to allow complete requirement of EAA’s
• e.g. baked beans on toast

*you dont’ have to consume all AA in the same meal. You can diversify over many meals because we know the body is under constant degradation. It’s an overall AA balance we’re looking for.

Complementary Foods

Cereals

• low in lysine
• sufficient methionine and cysteine

Legumes

• surplus of lysine
• deficient in methionine and cysteine

Digestion

• Cooking ‐ denatures proteins
• Secondary structure
• Fibrous material
  • Approx. 90% digestibility

Not All Proteins Are Created Equal: Limiting Amino Acid’s

• If a diet is inadequate in any essential amino acid, protein synthesis cannot proceed beyond the rate at which that amino acid is available. This is called a limiting amino acid. [the importance of getting EAA’s for maximising muscle growth]
• An essential amino acid present in insufficient quantities for protein synthesis to take place
• Limiting AA is the one that runs out first
• These are known as limiting AA. These are limiting AA in the context of not having them elsewhere. That’s why we have to make sure we consume foods that have them in them.

Limiting Amino Acid

C is the limiting amino acid in this example because R and A are left and we can’t continue to make CAR PRO’s because there is no more C PRO.

Protein‐Energy Malnutrition (PEM)

• PEM exists predominately in underdeveloped nations
• Mainly children….Why? Because they’re relative PRO intakes are highest in the first years of life: 2.5-3 g/kg
• WHO estimates 500 million children suffer from PEM
  • 40,000 will die each year
  • Adults in Western nations

HIV/AIDs and renal failure: Difficult to determine if due to insufficient protein or energy or both

• Kwashiorkor occurs around 2 y/o after breastfeeding has stopped as they are weaned onto malnutrished diets with low quality/quanitity PRO
• The liver is not receiving enough AA’s to make PRO as a result of that because PRO is important in osmotic regulation children end up with edema (fluid in belly)

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Lipids

Week 6

Fatty Acids

Practicality: Being able to name a fatty acid (eg: Stearic acid) by looking at a pictorial representation isn’t really useful (or necessary). What is useful though, is being able to identify and apply the correct nomenclature (naming) to pictorial representations AKA being able to identify sat/uns/poly and which omega it is.

• Fatty acids are long chains of hydrocarbons ending in ‐ COOH
• Have an omega end and an alpha end (contains “OH” – the ‘acid’ end of a fatty acid).
  • The omega end is the end we start counting from when we are trying to determine how many Carbon atoms there are in the fatty acid, and where the double bonds are.
• Fatty acids may be saturated fatty acids or unsaturated fatty acids
• H provide energy 
• The chain length and amount of double bonds determines the type of fatty acid
• The location of the first double bond determines the ω type of fatty acid
• A double bond occurs when you lose a H because C needs to form a double bond somewhere
• Carbon must always maintain 4 bonds
• ω/n = omega

Saturated Fatty Acid
Structure (No double bonds)

• They’re called saturated because they’re saturated in H molecules.
• Makes the liver produce CHOL

Stearic Acid

E.G. Chocolate: Solid at room temperature and melts at 37C that’s why you shouldn’t put chocolate in the fridge because it changes the chemical structure and texture.

Monounsaturated Fatty Acid Structure (1 Double Bond)

Oleic Acid

• No matter how many C it has if it only has 1 double bond it is a monounsaturated fat.
• The location of the double bond occurs at the 9th C hence it’s an Omega 9.
• The location of the double bond cant change

Polyunsaturated Fatty Acid
Structure (≤2 Double Bonds)

Linoleic Acid

• The first double bond occurs at the 6th C (hence it’s an omega 6 fatty acid)

Chain Length of Fatty Acids

Long chain FA: > 12 Carbons *usually used for energy

Medium chain FA: 6 ‐ 10 Carbons (e.g. animal/dairy)

Short chain FA: < 6 Carbons (produced via fermentation, e.g. vinegar which is only 2 C long. SCFA often have a strong smell and tend to arise when bacteria break down fatty acids commonly in the LI (e.g. butyrate).

Remember: All oils/fats have all fats in them. It’s about the prominent fat which determines its name.

Fatty Acids In Foods

Saturated Fatty Acids

• Predominantly in animal products, but also palm oil and cocoa butter
• 11‐12% of total daily energy intake

Most common;

• Palmitic acid (C16:0) (30g/day)
• Stearic acid (C18:0) (14g/day)

Monounsaturated Fatty Acids

• Can be synthesised by both plants and animals
• Most common in nature & our body;
• Oleic Acid (C18:1ω9) (37g/day)
• Foods‐ Olive, Canola, Peanut Oils and milk fat, beef fat
  and sheep fat

Polyunsaturated Fatty Acids

• 6% of total energy intake
• Liquid at room temperature

ω ‐3 Family:

• (alpha‐linolenic acid, C18:3 ω 3) (2g/day)
  • ALA can be converted (poorly) to EPA by adding extra double bonds and lengthening the chain but still remains an O3
• Foods‐ Flaxseed, Walnut, Canola Oil and small
  amounts green veg’s.
• Eicosapentaenoic acid (EPA) (20:5 ω 3) 0.1g/day
• Docosahexaenoic acid (DHA) (22:6 ω 3) 0.1g/day
• Foods‐ fish, fish oils (the oilier the fish and colder the fish lives in the more EPA/DHA)

ω‐6 Family:

• (linoleic acid, C18:2 ω 6) (17g/day)
• Foods‐ Safflower, Sunflower, Corn, Soy, Grapeseed
  and many other oils

Hydrogenation of Fatty Acids

• Process used to solidify an oil to make them solid at room temp = better for spreading
• Addition of H to C=C double bonds
• Hydrogenation forms a trans fatty acid

• Creates a partial double bond
• Trans form is straight instead of kinked and they behave like sat fat inside our body

FAT – You are what you eat

• What you store in your adipose tissue is derived predominately from the fat you eat. (A justification for low fat high carb classic body building style diet – refer to ‘Turning Carbohydrates to Fat:de‐novo lipogenesis’.
• Stearic acid is mostly converted to oleic acid

Fatty Acid Omega Families

• Only plants can introduce new double bonds
  between the omega end and the ω‐9 bond
• All animals can further de‐saturate by adding more double bonds and elongate fatty acids by adding more C’s

Fatty acid families;
ω ‐9
ω ‐6
ω ‐3

Essential Fatty Acids ‐ Linoleic (O6) & Linolenic acids (O3)

• Deficiency = growth retardation, skin lesions, reproductive failure and visual problems
• Essential fatty acids are involved in vision and the immune system
• Rarely used for energy predominantly used for cellular function

The function of ω-3 is dependent on the ratio of ω-6:ω-3

ω ‐6 fatty acids (linoleic acid)

• major metabolite = arachidonic acid (C20:4n‐6)

ω ‐3 fatty acids (linolenic acid)

• major metabolites = eicosapentaenoic acid (EPA) (22:5n‐3) and docosahexaenoic acid (DHA) (22:6n‐3)

These fatty acids are synthesised by the same elongase and desaturase enzymes in many tissues

Omega‐6 (Linoleic Acid)

Omega‐3 (alpha‐Linolenic acid)

Pro versus anti‐inflammatory

Typical western diet includes more O6’s than O3.

Synthetic Pathways

• Fatty acids are transported to liver
• Elongated and desaturated in order to convert them to arachidonic acid, EPA, DHA

Where Do Fats Go?

Function:

• Energy production: Most of the fat that sits in our tissue is going to be liberated for energy production at some point
• Membrane structure and function: EPA/DHA enter cell membranes to help produce hormones or help regulate the immune system
• Eicosanoid formation related to the inflammation process

• Arachidonic acid and EPA compete to be converted into eicosanoids
• While fat utilisation for energy production is a slow process this is not true for eicosanoid production – it is fast
• Eicosanoids are a signalling molecule that responds to stress/inflammation and immediate function. Important for smooth muscles and blood pressure regulation.
• Eicosanoid tends to promote vasoconstriction and vasodilation depending on the type of omega fatty acid.
  • O6 usually IN blood pressure
  • O3 usually DE blood pressure 
• The practicality of this is people with higher levels of O3:O6 have an association with a lower risk of heart attack.

Essential fatty acids generate Eicosanoids

EFA’s generate eicosanoids which are known as thromboxanes and leukotrienes.

Eicosanoids

• Derivatives of 20‐carbon fatty acids;
• Affect cells where they are made;
• Have different effects in different cells (e.g. muscle contraction & relaxation)
• Help regulate blood pressure, blood clot formation, blood lipids, and immune response;
• Participate in immune response to injury and infection, producing fever, inflammation, and pain.
• Include: prostaglandins, thromboxanes, leukotrienes

Eicosanoids Have Different Effects

• Omega‐6 eicosanoids: derived from Arachidonic acid:
  • increase blood clotting (why Inuits have lower blood clotting and bleed because they have very low levels of O6).
  • increase inflammatory responses
• Omega‐3 eicosanoids: derived from DHA, EPA:
  • anti‐inflammatory, antithrombotic, antiarrhythmic, hypolipidemic, vasodilatory properties
• A role in mitigating: Ulcerative colitis, Crohn’s, Cardiovascular disease, Type 2 diabetes

Triglycerides

• Tri because it has 3 fatty acids per molecule
• 95% of fatty acids in food are stored in our body is as triglyceride
• The main form of lipid found in the food we eat
• Has a glycerol backbone which is synthesised from glucose
• Cleared out of bloodstream within a couple of hours

Stereospecificity 

Referring to the positions of the fatty acids

• Position 1; saturated fatty acid
• Position 2; unsaturated fatty acid (C16‐18)
• Position 3; random

Structure of Triglycerides

It’s a two way straight of synthesis and hydrolysis.

Binding two amino acids together require a condensation reaction.

• Triglyceride formation = Glycerol + 3 FA’s = triglyceride via a condensation reaction.
• When we pull apart a triglyceride it’s done via a hydrolysis reaction

Phospholipids

• Derived from diet
• Found in cell membranes
• Synthesised from triglycerides 
• Hydrophilic which enables fat to be stable/mix in a watery environment
• One fatty acid substituted by a phosphate group
• Common example –Lecithin (phosphatidyl‐choline)
• Other phosphate groups
  • Phosphatidyl ‐ethanolamine, serine, inositol
  • Foods ‐ egg yolks, liver, brain, wheat germ and peanuts
  • Emulsifier
• Structural component of cellular membranes, together with cholesterol

Phospholipids form

Phospholipid head = hydrophilic / tail = hydrophobic

Phospholipids are a major
component of cell membranes

• Bilayer = two layers of phospholipids give the cells membranes structural integrity
• Smooth muscle contains a lot of O6 and O3 contained within these phospholipid bilayers

Sterols

In these phospholipid bilayers, there are sterols which are FA’s that have been modified by the liver to produce ‘rings’ (a description of the chemical structure)

• A multi‐ringed structure
• Do not have a glycerol backbone
• Waxy substance
• Do not readily dissolve in water
• Cholesterol and Vit D are sterols
  • Cholesterol starts out as a SAT fat and is found in every cell membrane because it assists in regulating cell function 

Functions of Cholesterol

• An essential component of cell membranes
• Produced by the liver
• Found only in animal products
• Endogenous CHOL intake has minimal effect on serum CHOL because higher intake of CHOL signals the body to make less CHOL exogenously. 
• Precursor to synthesis of: Estrogen, testosterone, vitamin D, cortisol
• Precursor to bile acids (large user of CHOL)
• body manufactures 800‐1500 mg/day
• dietary sources contribute 300‐450mg/day

How Soluble Fiber May Lower Cholesterol

Soluble fibre forms a gel which binds some CHOL in the SI and transports it out of the body.

Soluble fibre also binds to bile

Lipid Digestion

Summary [Video]

1. Lipid digestion primarily occurs in the SI (small amount in the stomach)
2. Lipases break down TRI and phospholipids
3. Gastric lipase hydrolysis a small amount of TRI into fatty acids and monoglycerides
4. Bile is released into the SI and clings to the mono, di and triglycerides of fat globules causing them to break up into TRI emulsion droplets (most of the TRI we consume are broken down in the duodenum)
5. Pancreatic lipase attaches to TRI molecules of the emulsion droplets
6. Each TRI molecule is broken down into monoglycerides and fatty acids
7. Bile salts form tiny cells known as micelles which attract fatty acids, monoglycerides, phospholipids and CHOL to the epithelial cells of the SI
8. These fatty acids, monoglycerides and some phospholipids and CHOL pass freely across the epithelial cells
9. Micelles re-enter the chyme and continue to transport these ends products to the SI epithelial cells
10. Within the epithelial monoglycerides are commonly broken down further by lipase producing glycerol and fatty acids
11. Glycerol and fatty acids then re-combine to form TRI
12. These TRI then join with phospholipids and CHOL to form chylomicrons
13. Chylomicrons leave the epithelial to transport into the bloodstream via the lymphatic system

 

Stomach: Churning action

Small Intestine: Emulsification, Breaking Off of Fatty Acids & Absorbing 

• Bile (emulsifies)
• Pancreatic Lipase (enzyme break down)
  • Chops off FA’s to create free fatty acids
• Phospholipase A2
• Cholesterol esterase

Mix with bile ‐ mixed micelles

Digestion of Lipids

• Large fat droplets get broken down into small fat droplets
• Pancreatic lipase breaks down FA’s into free FA’s.
• FA’s are absorbed through facilitated transport
• We think the absorption of fat doesn’t cost energy

Sequential digestion of triglycerides

• Removal of fatty acids at positions 1 and 3 (~100% complete)
• Fatty acid @ 2 (~ 50%)

Phospholipase A1 and A2: Hydrolyzes fatty acids from phospholipids to be absorbed

Cholesterol esterase: Hydrolyzes fatty acids from cholesterol esters

Lipid Absorption

• Fatty acids brought into enterocyte (SI cell) where FA’s are converted to TRI known as esterification 
  • This is done because you can pack a lot of energy into a TRI compared to anything else
• TRI is packaged into a delivery protein called a lipoprotein (contains lipid + PRO) which allows fat to be delivered around the body
• The lipoproteins humans generate in the enterocytes of the SI are known as chylomicrons (contain fat, CHOL and phosphates)
• Chylomicrons have a single lipid bilayer which is released into the lymphatic system and drains through the lymphatic system into the bloodstream and then to be used/stored.
  • We see an increase in chylomicrons at about 30min post-meal. Higher fat = more chylomicrons [explains the example the game changers used with the cloudy blood after a fattier meal]

Glycerol & Short Chain fatty acids

SCFA’s don’t go into the chylomicrons they enter the portal bloodstream where they are used by the liver. The rest of it (monoglycerides, FA’s, CHOL, phospholipids) is reesterified (put back together) inside the chylomicron. On the outer surface of the lipoprotein is a specific target and the major target signalling protein is known as an apolipoprotein (main one known as principal apolipoprotein B48) which acts as a conductor to tell chylomicrons where to go.

• Passive diffusion
• Enter the portal blood stream

Monoglycerides, fatty acids, cholesterol, phospholipids

• Re‐esterified
• Chylomicron
• Principal apolipoprotein B48
• Microsomal triglyceride transfer protein (MTP)

Lipid Transport ‐ Dietary Lipids

Chylomicrons

Contain a range of apolipoprotein. 

• Apolipoproteins;
• A (I & IV), B48, C (II & III), E

Role

• Delivers triglyceride to peripheral tissues
• Apolipoproteins C2 activates an enzyme found in our adipose tissue – that enzyme is…
• Lipoprotein lipase (LPL) cleaves triglycerides in core releasing fatty acids
• apoCII
• Fatty acids diffuse into the cell
• Remnant cleared by the liver
  (apo B48 & E)

Summary: We break TRI down twice and put them back together twice

1. You start with a TRI and break it apart 
2. You synthesise it as a TRI inside your SI cells
3. Deliver to adipose tissue which then breaks them apart into FA’s
4. Inside adipose tissue, you synthesise them back to TRI

Measuring Chylomicrons: VLDL, LD & HDL

• Chylomicrons are the most buoyant of the fat fractions because they contain the most fat which is why they float to the surface 
• VLDL contains less TRI but more CHOL because its role is to deliver CHOL to the entire body
• VLDL turn into LDL: LDL contains a lot of CHOL because they live in our bloodstream for 24h~ and their role is to transport CHOL to the entire body which is why people consider them typically ‘bad’ because they have a powerful role to deliver to all tissues
• HDL is the most dense. HDL takes CHOL back via reverse CHOL transport (back from tissues to liver) which is why it’s considered ‘good’. 

Lipid Transport ‐ Endogenous Lipids

Very Low Density Lipoproteins (VLDL)

• Synthesised by the liver
• Contain: repackaged lipids and synthesised lipids phospholipids and cholesterol
• Converted rapidly into LDLs

Apolipoproteins:

• B100, C & E
• Hydrolysed by LPL and becomes VLDL remnant
• Fate of VLDL remnant;
• cleared by liver ‐ LDL

High Density Lipoproteins 

• Synthesised by the liver, kidneys and muscle
• High protein, low triglyceride
• Involved in reverse CHOL transport 

Apolipoproteins:

• A1, A2 and A3
• Removes cholesterol from peripheral tissues and transfers to other lipoproteins ‐
• Reverse Cholesterol Transport
• Cholesterol ester transferase protein
• Cleared by the liver

Adipocytes (Fat Cell)

Within our adipose tissue, we have adipocytes.

• Adipocytes multiply when full by splitting in half. When they split they’re smaller than the original fat cell they came from but they can then fill up to the original size they came from.
• Once you have a fat cell you can’t get rid of it – we’re born with a certain # of fat cells variable to each person and largely dependent on mothers fat intake when she’s pregnant. Does that just apply to fat cells you’re born with or fat cells you gain over lifestyle changes? Adipocytes increase/decrease in size when you lose body fat but will never go away, they’re just less full.
• Could this infer limitations to a morbidly obese person reaching certain low levels of body fat %? I.E. A person has that many fat cells from being morbidly obese cannot reach x low % of body fat because no matter how small the adipocytes get there are just still too many of them to allow one’s body composition to reach x low %? Inferring that there could be a rate limiter put on the ability to reach a specific low relative fat % ONCE you reach a certain threshold of obesity (total number of adipocytes)?
  • To be truthful, I’m not sure, but my thinking is probably not. Given cells are microscopic, and that you could essentially have an ’empty’ adipocyte, even a person who was morbidly obese could probably attain a certain body fat percentage. The bigger issue is more often the skin flaps that arise after enormous weight loss which often require surgical removal. When this happens, the adipocytes present at the site of removal would also be removed via liposuction. – Adam Walsh

• 90% of cell volume of adipocytes is lipid droplets thus they have a massive capacity for triglyceride storage increase or decrease in size
  • This likely explains why 1kg of fat doesn’t = 9000 calories (9g x 1000g) because adipocytes aren’t 100% fat.
• FFA re‐esterified to TG
• Imported into lipid droplets

Glucose Uptake in Adipocytes: Turning Carbs Into Fat? 

• Insulin activates adipocyte GLUT4 AKA the key driver of glucose uptake into adipose tissue is GLUT4 transporter 
• Most of the glucose going into the adipocyte is being converted and stored as glycerol (a backbone of a TRI). 
• Remember it’s about converting glucose into glycerol, while glycerol is part of a TRI is technically not actually a fat. So CHO don’t get directly converted to fat they help form the backbone of a TRI.

Fat Storage: Complete Picture

1. FA’s being absorbed across intestinal cells where they’re repackaged into chylomicrons into the lymphatic system than bloodstream
2. Chylomicrons are cleaved by lipoproteins lipase so FA’s can get into adipocytes
3. Reassemble FA’s into TRI and store them. But they can be broken down via lipolysis (driven by hormone-sensitive lipase) when we need fat for energy.
4. LDL produced from VLDL which is packaged in the liver and used to transport CHOL throughout the body.
5. Liver is taking remnants of chylomicrons and HDL in the liver – the process of recycling HDL, chylomicrons and CHOL. Excess CHOL is excreted in bile and recirculated again and again because our bodies prefer to hang onto it.

Storage Capacity of Lipids

450,000 = 107,553 Cals

Energy Storage

• You must have O2 on board to produce ATP from fat.

Stored Fat vs Dietary Fat Energy Difference

• Dietary fat = 39kj/g (9.2 cals)
• Stored Fat = 36kj/g (8.5 cals)
  • There is a difference because there is a small amount of water, protein and other constituents in stored fat.

Lipids and Health ‐ Heart Disease

Heart disease is both: Coronary Heart Disease & Stroke

• Both caused by atherosclerosis
• Atherosclerosis results from the formation of fat and cholesterol-laden plaques on blood vessel walls.
• A plaque calcifies to form an atheroma
• The risk is less to do with the presence of the plaque being there but due to a part of the atheroma dislodging or occluding (blocking blood) flow where it can end up in your brain and cause a stroke or block off a blood vessel entirely and cause a heart attack.

Heart Disease ‐ Coronary Heart Disease

CHD is the end stage of a longstanding condition

Manifestations;

Myocardial ischaemia (Angina): Blood flow through coronary arteries is reduced by atheroma

Myocardial Infarction (Heart Attack): Blood flow is insufficient to allow cellular function and damage often irreversible

Stroke: Atheroma lodges in the in the cerebral vasculature

Heart Disease ‐ Causative Factors

4 major lipid variables (all independent risk factors):

• Total cholesterol (threshold value <5.5mmol/l)
• LDL‐cholesterol
• HDL‐cholesterol
• TG levels
  • High TRI infers you have a chronic fat intake.

Aetiology: How Heart Disease Occurs 

• LDL filter into vascular tissue where a proportion become oxidised and are taken up by white blood cells (macrophages)
• They form foam cells – foam cells become calcified which turns into an atheroma

• When you get narrowing of your blood vessels you get damage and it’s that clotting process that can be fatal.
• A diet high in O3 helps reduce clotting and high O6 increases clotting and high in sat fat can enhance clotting of CHOL plaques

Summary of CHO, FAT & PRO Lectures

 

• CHO broken down into glucose
• Fat broken down and transported into chylomicrons
• PRO converted to AA’s

% of ‘Stored’ Energy

Protein isn’t technically stored it’s just what our muscles are made of.

Summary of Each Energy Substrate In Each Tissue

TCA = citric acid cycle/krebs cycle / TO = Triglyercide / Acetyl-CoA is a precursor to ATP production

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Energy Metabolism Biochemistry

Week 7

Components of Energy Expenditure

1. Basal metabolism (BMR)

• Comprises ~2/3’s of daily energy expenditure in average person
  • Compromises of respiration, blood transport, enzymatic processes,
• Lean body mass largest determinant
• Supports the basic processes of life

Resting metabolic rate (RMR) is a measure of energy output and is slightly higher than BMR

TEF: Energy used to digest, absorb and transport food.

 

Factors Affecting BMR

Increases

• Height: the taller, the higher the BMR
• Growth (pregnancy, childhood)
• Fever and stress
• Higher muscle mass/lean tissue (males typically higher than females)
• Smoking and caffeine
• Environmental temperature (heat and cold raise BMR)

Decreases

• Ageing (loss of lean body mass)
• Fasting/starvation
• During sleep

Overview of Metabolism

• Glycolysis: conversion of glucose to pyruvate to produce ATP (can occur in aerobic or anaerobic capacities)
• Two key pathways that occur within the mitochondria: citric acid cycle (CAC) and oxidative phosphorylation (OP) invoking electron transport
• The citric acid cycle is an oxidative pathway (aerobic) that can result in a high amount of ATP
  • Substrates are produced: NADH and FADH (electron carrierers that contain Niacin). They carry electrons into the oxidative phosphorylation pathway. In this process the majority of ATP is re-synthesised.
  • Half of your body weight in ATP is used every day – that’s how much we use
• The use of ATP results in the formation of ADP back and forth via the CAC and OP
• OP is an ADP recycler which gives us back ATP
• Key pathways occurring in the mitochondria are the CAC, electron transport chain and OP

Glycolysis

• Can occur with or without O2
• Start with glucose and end up with pyruvate 
• Two ATP are used just to start the glycolysis process so we’re in a net ATP deficit
• Purple box = where we create ATP as well as an electron carrier
  • NAD+ is converted to 2 NADH (NADH contributes to energy production via oxidative phosphorylation) 
  • ADP is recycled into ATP
• Glycolysis seems to use 2 ATPs and produce 2 ATPs but it actually produces a total of 4 ATPs because the purple box sequence of events occurs TWICE to create a net energy positive balance.
• Most of the energy we derive comes from the CAC and electron transport whereas glycolysis is a pretty low yield energy pathway netting only 2 extra ATP.
• Pyruvate has two potential fates:
  1. Get’s converted to Acetyl-CoA
  2. Converted to lactate (when O2 is limited)

Pyruvate’s Options

Pyruvate is the end product of glycolysis – it has two metabolic fates:

1. Conversion to lactate (anaerobic process)
2. Conversion to acetyl CoA (aerobic process)

once pyruvate has been converted to acetyl Co-A, it can’t be converted back to pyruvate (unlike the pyruvate-lactate process).  You’ll notice that the Hydrogen atoms are once again taken to the Electron Transport Chain by co-enzymes, while acetyl Co-A heads off to the TCA (tricarboxylic acid) cycle.  If this is the cycle that occurs then 1 glucose molecule gives us 2 pyruvate molecules which gives us 2 acetyl Co-A molecules.

Pyruvate -> Lactate

• Occurs when O2 is limiting (e.g. sprinting) or cells lack sufficient mitochondria
• Lactate formed when hydrogen is added to pyruvate which is a critical process as allows regeneration of NAD+, which keeps glycolysis running
• Liver cells recycle muscle lactic acid (lactate) through the Cori cycle

Citric Acid Cycle (Krebs Cycle) Simplified

• Now we’re talking about what happens after glycolysis to Acetyl-CoA in the citric acid cycle
• CAC requires O2 and is responsible for creating energy during aerobic activity
• Acetyl-CoA = central molecule for energy metabolism 
• Lot’s of Acetyl-CoA coming into the CAC and lots of NADH’s (electron transporters) being pulled out

1. The TCA cycle starts with Oxaloacetate which is made primarily from pyruvate.

2.  Oxaloacetate picks up acetyl Co-A and undergoes transformations along the cycle that releases 8 Hydrogen atoms and their electrons to the Electron Transport Chain.

1. Oxaloacetate is sythesised in the last step of the TCA cycle allowing it to continue (it picks up another acetyl Co-A).

2. Acetyl Co-A in the TCA cycle can be made from any of the macronutrients we discussed earlier.

Electron Transfer in Metabolism

This diagram is the heart of energy production it’s all about: pulling electrons from glucose, fatty acids and amino acids – shunting those electrons inside the mitochondria where they can re-synthesise ADP back into ATP 

• Starting with glucose electrons and protons are removed through glycolysis (pink arrow down)
• These are carried into the mitochondria
• Those electrons and protons drive the re-synthesise of ADP into ATP

Electron Transport Chain

The Electron Transport Chain is the final part of the energy pathway. You’re back at the mitochondria now and the synthesis of ATP energy.

1. NADH and FADH are passed along the electron transport chain and their electrons and protons are released to protein complexes known as cytochromes which live within the mitochondria
2. Electrons are used to pump H+ which allows a build-up of protons
3. Because of the large number of protons building they can move outside the mitochondrial space
4. ATP synthase drives the re-synthesis of ADP back to ATP
5. The end products of oxidative phosphorylation = ATP, H20 and CO2

Summary: electrons are passed into the mitochondria allowing a build-up of electrons allowing a re-synthesis of ADP into ATP via ATP synthase. 

Glucose Metabolism Balance Sheet

• Consider the CAC produces the most ATP because of the high yield of 6x NADH = 2.5 ATP each
• We spent 1 glucose molecule and 2 ATP in glycolysis to create 32~ ATP 

Metabolism of Lipids

Fatty acid metabolism occurs through beta oxidation. 

Starting with Triglycerides

• Triglycerides hydrolysed by hormone‐sensitive lipase (HSL) is called lipolysis which produces fatty acids and glycerol
  • Hormone-sensitive lipase activity is increased when fasting

Glycerol

• Converted to glyceraldehyde‐3‐phosphate to enter glycolysis to either form glucose (gluconeogenesis) or convert to pyruvate. This is how fats can be used to produce energy.

Fatty Acids

• Fatty acids converted to acetyl CoA and those reactions are called fatty acid beta oxidation

Fatty acids cannot be used to synthesise glucose as acetyl-CoA cannot be converted to pyruvate BUT glycerol the backbone of TRI can be converted to glucose or pyruvate and used as energy.

Summary of Beta Oxidation

• The process of beta oxidation is the process of cleaving off 2 C at a time
• Every time we cleave of 2 C it produces 1 Acetyl-Coa, 1 NADH, 1 FADH
• An 18 C fatty acid produces 40 ATP via the electron transport chain. In total 110 ATP can be produced from NADH, FADH and Acetyl-CoA. This is how  fat is such high energy yielding molecule.

 

1. Hydrogen atoms are taken to the electron transport chain by co-enzymes,

2. Co-enzyme A ‘attaches’ to the fatty acid chain to break off two Carbon atoms (thus forming acetyl Co-A) and heads off to the TCA cycle.

3. This process shortens the fatty acid by 2 Carbon atoms each time

Interrelationships of Metabolism

• Important: all pathways lead to Acetyl-CoA eventually. The potentiual energy in the food we eat is unlocked because Acetyl-CoA can be oxidised through the CAC and the electron transport chain.
• Glucose, fatty acids and amino acids can all be transformed into Acetyl-CoA to be oxidised and for energy production via the CAC and the electron transport chain.

Amino Acids

• When we look at this figure, we can see that when amino acids are converted to pyruvate, this describes glucogenic amino acids.  This is because pyruvate can be converted back to glucose.  In this process, the Hydrogen atoms are taken to the electron transport chain by co-enzymes.  Some amino acids are taken straight to the TCA cycle – they are also known as glucogenic amino acids.
• On the other hand, ketogenic amino acids are converted to acetyl CoA which is irreversible.  Acetyl Co-A then heads off to the TCA cycle.

Note: py

rvute: theoretically we can make AA’s out of substrates other than PRO however it is very limitied and can only make glucose -> pyrvuate -> converted into alanaine.

Lactate can be transformed back into glucose in the liver via the kori cycle (lactic acid cycle) depending on metabolic depends.

The cori cycle is where you expect to see the most electron carriers produced from the metabolism of a single molecule of glucose and where you’d see the most activity from during intense physical activity

Glucose Oxidation after a Meal

Summary: Glucose enters glycolysis pathway > converted to pyruvuate > converted to Acetyl-CoA to produce ATP.

After a mixed meal, approximately half of the ingested glucose is used for glycogen synthesis (storage) (liver and muscle)

After a mixed meal, when blood glucose is high, Glucose oxidation is increased

Fate of Excess Glucose: Glucose Promotes It’s Own Oxidation

1. Energy source

• Insulin activates pyruvate dehydrogenase
• Excess glucose results in the almost complete use of glucose as an energy source (glucose intake and storage promotes its own oxidation)

2. Conversion to fatty acids or amino acids

• De novo lipogenesis (CHO to fat conversion) is limited to the liver and is a minor pathway in humans. It’s difficult to convert CHO to fat you have to eat a very large amount of calories/CHO to make that happen in any considerable way. Why? Because the body will preferentially oxidiase glucose the more that glucose is ingested. Thus instead of utilising the fat we are eating we are likely going to store it straight away because we’re utilising the glucose we’re eating.
  • What we really do with glucose in relation to fat conversion (de novo lipogenesis) is it get’s converted to glycerol (the backbone of a TRI).

Lipid Oxidation after a Meal

Unlike glucose, lipids do not promote their oxidation after a meal – they are just stored.

Why?

• Beacuse there is no direct regulatory interactions between fat oxidation and fat intake.
• This is likely because our capacity to store fat is theortically endless compared to glyogen storage which has a max capacity.
• Little requirement to minimise chylomicron (lipoproteins humans generate in the enterocytes of the SI) concentrations because they pose no significant harm.
• Virtually unlimited capacity for lipid storage
• Preferential flow to adipose tissue in pulling apart and putting back together TRI
• Fat balance is regulated via storage over the longer term
• Fat in excess of energetic requirements will be stored

Metabolism of amino acids

• The body’s first preference for protein is to use it for structure and function, not energy.  In the face of excessive protein (or limited carbohydrate/fat intake), the body will use protein for energy.
• amino acids are deaminated (lose their Nitrogen group) before being used for energy.

 

From Feast to Fasting

Acetyl-CoA is converted to ketones.

• Below the doted line = the response to those hormones.
• Another example of how maximum fatty acid oxidation occurs in the 18-24h period of a 24h fast.

 

---

Water‐Soluble Vitamins

Week 8

Vitamins: Form & Function

Vitamins, by definition are an essential micronutrient that cannot be synthesised (either at all, or in enough quantities).

Essential organic substances needed in minute amounts by the body to perform specific functions ‐ 13 vitamins in total required

Water‐Soluble (B’s & C’s): B-Group, B6, B12, C

Most are water–soluble, meaning they dissolve in water.

• 8 B‐group vitamins involved in energy production (thiamin, riboflavin, niacin, biotin, pantothenic acid)
  • Note: Why is there not 12 B vitamins? They used to think there were, but they reaslised the vitamins they thought were B vitamins were just a different variety of B vitamin or just not a B group vitamin.
• Pyridoxine (Vitamin B6)
• Folate (B group vitamin)
• Vitamin B12
• Vitamin C

Fat‐Soluble: A, D, E, K

• Require a functional fat digestion and absorption process to occur.
• Fat-soluble vitamins are most abundant in high-fat foods and are much better absorbed into your bloodstream when you eat them with fat.

You DO NOT need to know NRVs for examination purposes – they are given in lecture notes as a reference source

Who Needs Vitamin and Mineral Supplements?

People with the following:

1. Inadequate food intake (elderly, restricted diets)
2. Increased nutrient requirements (pregnancy/lactation [exercise/athlete])
3. Some vegetarians
4. Chronic excessive alcohol consumption
5. Increased metabolic demands (surgery/trauma/fracture)
6. Maldigestion or malabsorption (liver disease, GI disease)
7. Primary prevention of disease (folate, thiamin)

Nutrient Losses

Organic nature of vitamins means they can be destroyed by exposure to light, oxidation, cooking, and storage

Methods to minimise nutrient losses:

• Refrigerate fruits and vegetables
• Store cut fruits and vegetables in airtight wrappers or closed containers and refrigerate
• Use a microwave, steam, or simmer in small amounts of water. Steaming minimises vitamin losses because there is reduced cooking time and heat exposure.
• Save cooking water for other uses for leached vitamid/minerals from in water
• Avoid high temperatures and long cooking times: softer vegetables that have been cooked for longer will likely have higher nutrient losses 

USDA Table of Nutrient Retention Factors
www.ars.usda.gov/main/docs.htm?docid=9448

Water‐Soluble Vitamins

• B group vitamins (eight in total) and C
• Transported throughout the water medium of the body
• Limited storage in the body (except for B12)

B group vitamins involved in energy metabolism:

• Thiamin (B1)
• Riboflavin (B2)
• Niacin (B3)
• Pantothenic Acid
• Biotin

Thiamin (B1)

Thiamin (or Thiamine, or Vitamin B1) is an important B group vitamin from the perspective of energy production.  Thiamin is part of the co-enzyme thiamin pyrophospahte (TPP).  TPP participates in the conversion of pyruvate to acetyl Co-A.  You’ll recall from the last topic on energy metabolism, that acetyl Co-A is utilised in the TCA cycle.  Thus, thiamin deficiency results in pyruvate not being converted to acetyl Co-A and a reduction in energy (ATP) production. 

Thiamin has a central role in generation of energy from carbohydrate. One of the keys steps linking glycolysis to the citric acid cycle is the conversion of pyruvate to acetyl Co-A. The enzyme involved in that process is pyruvate dehydrogenase. Thiamin is a cofactor in that reaction. The active form of the cofactor is thiamin pyrophoisphate also known as TPP.

• Central role in generation of energy from CHOs
• Also involved in RNA and DNA production and nerve
  function
• 30 day storage capacity 
• Used to be known as B1

Active form is as a coenzyme:

Thiamin pyrophosphate (TPP)

• Transported by RBCs
• Excess quickly excreted in the urine like most B vitamins (often can turn urine fluro yellow which is a sign B vitamins are being exreted)

Coenzyme: Thiamin Pyrophosphate (TPP)

• Involved in a key enzymatic step in the production of energy from glucose
• Removes CO2 from CHOs and some amino acids (decarboxylation)
• Converts pyruvate to acetyl CoA
• Thiamin is a co-factor in the enzyme pyruvate dehydrogenase which is the enzyme involved in pyruvate to Acetyl-Coa.
  • Thiamin deficiency inhibits this key converstion reaction of glucose metabolism which results in increased levels of pyruvate. (More common in children)
• Involved in citric acid cycle and nervous system
• Hence the more energy you expend (e.g. exercise more) the more thiamin you need because its a co-factor in energy production 

Thiamin Deficiency Disorders

• Occurs when polished rice is the only staple or in severely malnourished individuals
  • Because thiamin is contained in the bran husk of grains
• Seen within one month (lowest vitamin store in the body)
• Rare issue in Australia

Wet beriberi

• Oedema, enlarged heart, heart failure
• Results from accumulation of pyruvate and lactate as it can’t be metabolised leading to vasodilation and fatigue
• Generally seen in active individuals due to increased glycolysis

Dry beriberi

• Weakness, nerve degeneration, irritability, poor arm/leg
  coordination, loss of nerve transmission

Wernicke‐Korsakoff Syndrome

Seen mainly in alcoholics because:

• Alcohol diminishes thiamin absorption
• Alcohol increases thiamin excretion
• Alcoholic often have a poor quality diet

1. Wernicke’s Encephalopathy (brain swelling) (WE)

• Nystagmus: involuntary eye movement; double vision
• Ataxia: staggering, poor muscle coordination; mental
  confusion, “drunken stupor”

2. Korsakoff’s psychosis (KP)

Confusion and loss of memory (seen by ‘story telling’ to hide
this)

Thiamin Fortification

• WE responds well to thiamin treatment, but KP does not
• Fortified flour used in Australia since 1991 (compulsory) for bread production – theory being that alcoholics will at least eat some bread products
• Evidence for decrease in WE and KP since 1991, but not
  elimination
• Put into beer???
• Most alcoholics drink beer Change in taste? Beer promoted as a ‘health food’?

Food Sources of Thiamin

• Found in a wide‐variety of foods
• Wholegrain foods, wheat germ, yeast, legumes, nuts,
  pork
• Fortified flour
• Deficiency is rare unless you have a restrictive diet of some sort
• RDI: 0.1 mg/1000 kJ

Riboflavin (B2)

Riboflavin (or vitamin B2) is another important B group vitamin from the perspective of energy production.  It is another case of the vitamin being part of a co-enzyme (or two in this case).  The co-enzymes are flavin mononucleotide (FMN) and flavin adinine dinucleotide (FAD).  These co-enzymes can accept and donate two Hydrogen atoms.  The TCA cycle and Electron Transport Chain are involved in this process – two Hydrogen atoms are picked up in the TCA cycle and dropped off at the Electron Transport Chain.

Riboflavin is involved in energy production in the electron transport chain, citric acid cycle and catabolism of fatty acids. Again, this is through the vitamin being part of a coenzyme. The two main coenzymes involved are (use abbreviations) FAD and FMN. Riboflavin’s involvment in the citric acid cycle is through the acceptance of electrons by FAD. The electrons accepted then move to the electron transport chain.

Involved in energy production in:

• Electron transport chain
• Citric acid cycle
• Catabolism of fatty acid

Coenzymes:

• Flavin adenine dinucleotide (FAD)
• Flavin mononucleotide (FMN)
• Oxidation‐reduction reactions – acts as oxidising agents (removal of an electron from substrates) are also part of B2’s role

Functions of Riboflavin

• Participates in beta-oxidation
• FMN shuttles hydrogen ions and electrons into the electron transport chain
• Metabolism of oxidised glutathione (antioxidant)
• Riboflavin is important in redox reactions in energy production

Deficiency of Riboflavin

Ariboflavinosis (occurs within two months) *note these dificiencies don’t directly relate to B2’s role in energy production

• Glossitis (inflamed tongue)
• Cheilosis (cracked lips)
• Stomatitis (inflammation of mucus in mouth)
• Alopecia (hair loss)
• Dermatitis

 

• Usually in combination with other deficiencies e.g. niacin, thiamin
• Deficiency rare – alcoholics, low dairy intake

Food Sources of Riboflavin

• Dairy products
• Wholegrains
• Liver
• Oyster
• Brewer’s yeast
• Sensitive to UV radiation (sunlight) ‐ that’s why you have dairy stored in paper or opaque plastic containers

Niacin (B3)

‘Niacin’ describes both nicotinic acid (niacin) and nicotinamide found equally in food.

Niacin is the third B group vitamin involved in energy production.  Niacin’s co-enzyme forms are nicotinamide adenine dinucleotide (NAD) and NADP (the phosphate form of NAD).  These two co-enzymes are central to pretty much every metabolic pathway related to energy production, most notably the metabolism of glucose, fat and alcohol.

Niacin is involved in almost every metabolic pathway related to energy production. Its involvemnt is through its actions as a coenzyme. The two main niacin coenzymes are NAD and NADP. Niacin coenzymes are involved in glycolysis, the citric acid cycle, the electron transport chain as well as the metabolism of alcohol.

Coenzyme functions as:

• Nicotinamide adenine dinucleotide (NAD)
• Nicotinamide adenine dinucleotide phosphate (NADP)
• Oxidation‐reduction reactions to produce energy

Involved In:

• Glycolysis
• Citric acid cycle
• Cori cycle (lactic acid cycle)
• Electron transport chain
• Alcohol metabolism

Absorption, Transport and Storage of Niacin

• Readily absorbed from the stomach and small intestine (active transport and passive diffusion)
• Transported from the liver to all of the tissues where
  it is converted to the coenzymes
• Niacin can also be produced endogenously from tryptophan (essential amino acid)
• ~50% of niacin in diet is from tryptophan and 50% from pre‐formed nicotinic acid
  • Trypophan an AA found in meats – hence a justfication for adequetly eating enough AA rich foods to maxise synthesis of niacin.

Deficiency of Niacin

The ‘4 Ds’ of niacin deficiency (pellagra) are:

1. Dermatitis ‐ most often occurs in sun exposed areas of face and upper extremity

2. Dementia ‐ from neuronal degeneration in the brain and spinal column

3. Diarrhoea ‐ associated with oedema and inflammation of the intestinal sub‐mucosa

4. Death

• Prevented with an adequate‐protein diet
• At‐risk groups: corn as main staple, poor diet, alcoholics

Exposed skin from tshirt has responded to UV light poorly

Food Sources of Niacin

•Eggs, meat, poultry and fish
•Liver
•Mushrooms
•Whole‐grain and enriched breads and cereals
•Nuts and all protein‐containing foods
• Niacin is heat stable; little cooking loss

60 mg tryptophan can be converted into 1 mg niacin

Pantothenic Acid (B5)

• Part of coenzyme A (CoA) which is a component of Aceetl CoA
• Essential for metabolism of CHO, fat, protein
• Deficiency is extremely rare
  • Found in almost all foods

Biotin

• Metabolism of CHO, fat, and protein via carboxylase reactions (the transfer of CO2 groups)
• Deficiency rare as found in most foods
• Avidin (found in egg whites) inhibits absorption and you have to eat more than a dozen raw eggs a day to cause this effect

B6 (Pyridoxal, Pyridoxine, Pyridoxamine)

• Main coenzyme form: pyridoxal phosphate (PLP)
• Important in AA metabolism and CHO metabolism (via glycogen breakdown)
• Involved in process of transamination (for AA synthesis) and destination (pull apart AA’s) reactions
• Synthesis of haemoglobin thus can be implicated to anaemia
• Niacin synthesis (from tryptophan)
• Synthesis of neurotransmitters (serotonin, dopamine, histamine and GABA)

B6 Absorption and Metabolism

• Absorbed passively
• B6 is stored in the liver and muscle tissue (good sources
  of dietary B6)
• Excess is excreted in urine

Deficiency of Vitamin B6

• Anaemia
• Dermatitis (related to niacin deficiency)
• Convulsion, depression, confusion
• Reduced immune response
• Peripheral nerve damage

Food Sources of Vitamin B6

• Meat, fish, poultry
• Whole grains
• Bananas
• Spinach
• Avocados
• Potatoes
• Heat and alkaline sensitive

RDI 1.5 – 2.0 mg/day (dependent on protein intake)

Folate (B9) & Folic acid

• During the process of digestion and absorption, folate has a methyl group added to it. This form of folate is inactive and it is in that form that it is trapped in cells. Vitamin B12 accepts the methyl group which activates both it and folate making them available for DNA synthesis. In red blood cell production DNA synthesis and division commences.
• Without folate DNA strands break and cell division slows. In this scenario, instead of haemoglobin synthesis beginning and slowing down DNA synthesis and cell division, RNA synthesis continues which results in a large cell with a large nucleus. Usually, the nucleus would leave the cell providing a small, mature red blood cell full of haemoglobin. Instead, we are left with irregularly shaped, large cells that contain a nucleus. A deficiency of folate or vitamin B12 can cause this to occur.

• Coenzyme form: tetrahydrofolate (THF)
• Action closely linked to that of vitamin B12
• Involved in DNA synthesis
• Transfer of single carbon units
• Synthesis of thymidylate (dTMP) needed for DNA
• Inhibited by anticancer drug methotrexate (also used for rheumatoid arthritis and psoriasis)
• Homocysteine metabolism to help aid the growth of new blood vessels.
  • High homocysteine levels are involved in inflammatory injuries of the blood vessels
• Neurotransmitter formation
• B10 and B11 = identical to folate
• Involvement in the prevention of neural tube defects

Folate or Folic Acid?

• Folate is the form found in food and represents the various biochemical forms of pteroyl glutamic acid (folicin; vitamin M; vitamin B9)
• Folic acid is the synthetic form of folate and used extensively in dietary supplements and food fortification (does not occur naturally in significant amounts)
  • Bioavailability of folic acid is 1.7‐times more than of folate in food 

Deficiency of Folate

Seen in late pregnancy, malabsorption syndromes and alcoholics

Results in:

• Megaloblastic anaemia (immature RBCs lose the ability to divide from impaired DNA synthesis)
• Absorption problems (from immature intestinal cells)
• Neural tube defects (NTDs)
• Possibly: CVD, ? Cancer, ? Alzheimer’s
• The cells most sensitive to a deficiency of dietary folate are cells that have a short life span and rapid turnover rate.

Megaloblastic Anaemia Link To Folate & B12 Deficiency

• Megloblastic = big and immature
• Normal RBCs loose their nuclei while megloblastic RBC’s still have it

Neural Tube Defects Link To Folate Defiency

Prevalence rate of 3 to 4% and cause of 22% of all infant deaths

Neural tube: the embryonic structure that eventually forms brain and spinal cord

2 Types of NTDs:

Spina bifida: (incomplete closure of neural tube at ~ 4 weeks gestation)

Anencephaly: (‘without a brain’)

Importance of folate before (preconception) and during early stages of first trimester. But more often than not mothers don’t find out their pregnant until after 4 weeks when a possible NTD has already been created.

Pre‐Conception Folate Supplementation

Reduction in NTDs by 70% with pre‐conception folate supplementation at 4 mg/day

• Voluntary fortification of food with folic acid began in Australia in 1995
• Mandatory fortification of breadmaking flour in Australia since 2009 (~140 μg/serve)

 

MRC Vitamin Study Research Group Lancet 1991;338:131‐137

NTD Prevalence in Australia

Food Sources of Folate

• Liver** a lot of Vit A which can cause birth defects in excess hence the recommendation to not recommend liver for those planning pregnancy 
• Bread (~140 μg/serve)
• Fortified breakfast cereals
• Grains, legumes
• Green, leafy vegetables
• Susceptible to heat, oxidation, ultraviolet light

RDI of 400 μg/day for non‐pregnant adults

Peri‐conceptual recommendation is for an additional 400 μg (1 month before and 3 months after conception)

Vitamin B12

Forms are cyanocobalamin, methylcobalamin, and 5‐ deoxyadenosylcobalamin

• Contains cobalt
• Only produced by bacteria which is why it’s only in animal products not plants
  • We thought B12 was actually in mushrooms but it was the cow maneur that fertilised the mushrooms and enriches the soil.
  • B12 is produced in the LI but of the absorption is in the SI.
• Involved in folate metabolism (removal of methyl groups
  from THF)
• Maintenance of the myelin sheaths
• Metabolism of short‐chain fatty acids so they can enter the citric acid cycle
• Synthesis of DNA

Absorption of Vitamin B12

• HCl and pepsin in stomach releases B12 from foods then binds to ‘R’ protein made by salivary glands
• Require ‘intrinsic factor’ (IF) produced by stomach (paritel cells) to bind to B12 to allow intestinal absorption
• Can be absorbed passively, but only at 1% efficiency
• As we age we absorb less Vit B12 because as we age we produce less HCL

Deficiency of Vitamin B12

Pernicious anaemia

• Clinically looks like folate deficiency (megaloblastic)
• Nerve degeneration, weaknessTingling/numbness in the extremities (parasthesia)
• Paralysis and death
• Usually due to decreased absorption ability
• Takes ~5 yrs on deficient diet to see nerve damage
• Deficiency risk in vegans, infants of vegan mothers, low HCl production, and malabsorption diseases (e.g. Crohn’s)
• Macrocytic anaemia and peripheral neuropathy are signs of B12 deficiency
• Taking folic acid supplement may hide pernicious amaemia because you’re gettinog adequate folate intake

Therapy for Ineffective Absorption (Malabsorption)

• Absorption affected by: gastritis, malabsorption syndromes, and in the elderly (from reduced HCl production)
• Megadoses of B12 to allow for passive diffusion but usually not enough to get us out of deficineicy because we are still malabsopbing most of it which means even with more dosage we still can’t absorb it
• Which is why one would need monthly injections of B12 required

Food Sources of Vitamin B12

• Synthesised by bacteria
• Animal products
• Organ meat
• Seafood
• Eggs, Milk
• Fortified soy
• Spirulina (algae) and mushrooms are other plant forms of Vit B12 but its bioavailability is much lower

B‐Group Food Sources: Summary

B‐Group Vitamin Food Sources

• Grains provides thiamin, riboflavin, niacin and folate
  • But we don’t want highly processed grains like polished rice which is the most commonly consumed form of rice. 
• Fruits and vegetables provide folate
• Meat group provides thiamin, niacin, vitamin B6 and
  vitamin B12
• Milk group provides riboflavin and vitamin B12

Polished Rice vs Unpolished Rice

Less Processed Brown Rice

• Typically, after farmers harvest their rice, it goes to a mill. There, it is cleaned and the husks are taken off the grains. At this point, it is referred to as “brown rice,” and it is full of nutrients, vitamins, minerals and protein. Rice at this stage is quite healthy to eat.
• However, most people now prefer to eat “white rice,” which is what comes out of the process of milling and polishing the rice. Once the husk has been taken off, there remain several very thin layers or coats of nutritious bran, which get removed during polishing to produce the beautiful, shiny, white rice that billions of people eat daily across Asia.
• each unpolished grain contains up to 10 percent more calories than polished grains

What Does Polishing Rice Do?

• Removes and mitigates vitamins like thiamin, riboflavin, niacin and folate
• polishing rice also reduces its protein content

Vitamin C

• Ascorbic acid (reduced form), dehydroascorbic acid (oxidised form)
• Synthesised by most animals (not by humans)
• Passive transport if intake is high
• Excess excreted

Functions of Vitamin C

1. Reducing agent (antioxidant)

• Has two hydrogens to donate to bind to free radicals
• Converted to dehydro form

2. Assists in Iron absorption

• By convertting Fe3 (feric form of iron) + to Fe2 (ferris form of iron found in meat) + (more absorbable)
• So Vit C taken with feric form of Iron (commonly found in plants) can increase the absoprtion of that plant based iron AKA taking Vit C with plants can increase iron bioavailability.

3. Synthesis of carnitine, tryptophan -> serotonin, thyroxine, cortiscosteroids, aldosterone, cholesterol -> bile acids

4. Immune functions

5. Collagen synthesis

Collagen Synthesis

• Enough Vit C helps produce healthy skin
• If we don’t have enough Vit C present we end up with weak connective tissue. E.G. skin that tears/cuts easily because proline is convertd to hydroxyproline in the prescence of Vit C.

Deficiency of Vitamin C

Scurvy

• Deficiency after 20‐40 days
• Fatigue, pinpoint haemorrhages
• Bleeding gums and joints

Rebound scurvy

• Seen rarely with immediate halting of megadose vitamin C supplements

Who is at risk?

• Infants, elderly men
• Smokers: decreased intake and incrased turnover
  • Smokers have double the RDI of Vit C compared to non-smokers

Common cold??

Symptoms: Pinpoint Haemorrhages (lots of red dots on skin), Bleeding gums

Vitamin C Toxicity

Toxicity Symptoms

• Nausea, abdominal cramps, diarrhoea, headache, fatigue and insomnia
• Hot flushes s and rashes
• Interference with some medical tests (e.g. diabetes), creating a false positive or a false negative
• Aggravation of gout symptoms, urinary tract infections and kidney stones
• In those with iron overload diseases (haemochromatosis)
• Upper level for adults unable to be determined but 1000 mg/day considered prudent though many studies show high 1-3g dosages being effective

Food Sources of Vitamin C

Easily lost through cooking bceause it is sensitive to heat

• Citrus fruits
• Potatoes
• Green peppers
• Cauliflower
• Broccoli
• Strawberries
• Romaine lettuce
• Spinach
• Sensitive to minerals iron and copper and will oxidise if exposed to oxygen which is why leaving an unpeeled organge out can decrease the Vit C
• How do inuits surivive: Enough Vit C in fish/fish eggs to stave off scurvy.

RDI for Vitamin C

• RDIs vary between countries (45 mg/day in Australia)
• 10 mg/day to prevent scurvy+35 mg/day for smokers
• Average intake by adult Australians is 124 mg/day
• Fairly non‐toxic (at <1 g)

Bogus “Vitamins”

Laetrile

• “Vitamin B17”
• Converted to cyanide, promoted as a cancer cure
• No evidence for effect
• Toxic if over‐consumed

Pangamic Acid

• “Vitamin B15”
• Claimed to work as an antioxidant
• Promoted by the Russians to cover for their widespread doping but claimed to have performance‐enhancing claims
• Has zero effect

B10 and B11 = identical to folate

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Fat-Soluble Vitamins (FSV): A, D, E, K

Week 9

• Not readily excreted; because of that they can cause toxicity
• Absorbed along with fat and require bile for digestion (don’t confuse that with that you have to have a fatty meal to absorb FSV)
• Concern for people with fat malabsorption
• FSV are transported (like fat in chylomicrons) in VLDL and LDL

Food Sources of Fat-Soluble Vitamins

Most Common: Liver and green vegetables 

A ‐ liver, fish oils, fortified milk, eggs, dark‐green leafy vegetables, yellow‐orange vegetables/fruits

D ‐ Oily fish (salmon, herring), egg yolks, liver, margarine (fortified)

E ‐ plant oils, wheat germ, sweet potato, peanuts, margarine, nuts & seeds

K ‐ liver, green leafy vegetables, broccoli, peas, green beans

Vitamin A

Two Forms:

1. Preformed Vitamin A (Retinoids)

• Retinoids (retinal, retinol, retinoic acid)
• Found in animal products
• More bioavailable because it doesn’t have converted like cartenoids do

2. Provitamin A (Cartenoids)

• Carotenoids (beta‐carotene, alpha‐carotene, lutein, lycopene, zeaxanthin, canthaxanthin – tanning pills)
• Must be converted to retinoid form
• Intestinal cells can split carotenoids in two to form retinoids (6 μg micrograms of beta‐carotene = 1 μg retinol)
• Found in plants 
  • Cartenoids is what gives fruits and vegetables their colour

Transport & Storage of Vitamin A

• Liver stores 90% of vitamin A in the body
  • Reserve is adequate for several months
  • Why liver is the most nutrient dense source of Vit A
• Transported via chylomicrons or VLDL to the liver
• Transported from the liver as retinol via retinolbinding protein (RBP) to target tissue
• Target cells contain intracellular retinoid‐binding protein (CRBP) and can have effects on epigenetics

Functions of Types of Vitamin A

Involved in growth, reproduction and vision.

• Retinol is needed for reproduction (sperm production and foetal development
• Retinoic acid supports growth and cell maturation, bone formation and gene expression
• Retinal is needed for night and colour vision

We can convert between the different forms so Vit A specific supplement doesn’t matter that much which one it is:

Retinyl esters <-> Retinol Retinal <-> Retinoic acid

Role Vit A Plays In The Visual Cycle

When light energy enters the eye, it reaches the retina cells. It is here that we find the pigment rhodopsin When the light energy hits the cells of the retina, retinal changes from its cis form to its trans form. The trans retinal can’t bind to opsin and the rhodopsin changes shape generating an electrical impulse. After the electrical impulse has travelled to the brain, most of the retinal is converted back to its cis form and rebinds with the opsin. Some retinal is oxidised to retinoic acid which isn’t involved in the visual cylce. These small loses of retinal mean we need to replenish our stores of vitamin A to ensure good vision.

Cones

• Responsible for vision under bright lights
• Translate objects to colour vision

Rods

• Responsible for vision in dim lights
• Translates objects to black and white vision
• The pigment in the cells of the retina = rhodopsin (protein opsin bound to retinal)
• Light changes cis‐retinal to trans‐retinal changing shape of opsin creating a nerve impulse. That nerve impulse allows us to see in low ligh
  • This process is why we need time adjusting from light to dark and dark to light because cis-retinal to trans-retinal causing that nerve impulse takes time.
• Fresh cis‐retinal is required otherwise night blindness results hence Vit A deficiency results in night blindness

Vitamin A Role In Cell Health & Maintenance

• Epithelial cells line the outside (skin) and external passages (mucus forming cells) within the body
• Retinoic acid influences how epithelial cells differentiate and mature
• Vit A very important for epithelial of lungs and gut to maintain healthy mucous membrane 
• Without vitamin A, cells will deteriorate and lose their integrity 
• Vit A Deficiency: Leads to xerophthalmia (major cause of blindness) and follicular hyperkeratosis (skin disorder)
• Vitamin A plays an important role in the immune system

Stages Of Xerophthalmia

World’s leading cause of non-accidental blindness

1. Conjunctival xerosis (dryness)
2. Bitot’s spots (plaque formation)
3. Irreversible blindness

Deficiency of Vitamin A

1. Night blindness (inadequate cis‐retinal)
2. Decreased mucus production
3. Bacterial invasion in the eye becomes easier because of poor epithelial integrity

Measuring Vitamin A

• International unit (IU) ‐ crude method of measurement
• Retinol activity equivalent (RAE) ‐ current, more precise method of measurement

1 μg retinol = 1 RAE = 3.3 IU = 6 μg beta‐carotene = 12 μg of other provitamin A

Toxicity of Vitamin A (3‐10 times the RDI)

Acute

• Ingestion of large dose(s) of vitamin A (within a short period) e.g. ~ 200 mg
• Result in intestinal upset, headache, blurred vision and muscular incoordination
• Symptoms disappear when supplements are stopped

Chronic

• Large intake of vitamin A over a long period e.g. ~10 mg/day for > 1 month
• Vision problems, Bone/muscle pain, loss of appetite, skin disorders, headache, dry skin, hair loss, increased liver size, vomiting
• Increased activity of osteoclasts (bone reabsorption) (causes weakened bones and contributes to osteoporosis and fractures

Teratogenic (birth defects: affects foetal development)

• Can produce physical defects on developing foetus e.g. spontaneous abortion, birth defects
• May occur with as little as 4 x RDI of preformed vitamin A taken in first trimester of pregnancy. Why they caution women not eating liver often during pregnancy.

Upper Level for Vitamin A: 3000 μg RE for adults

Cancer & Carotenoids

• Role in cell development, immune‐system and antioxidant activity
• Megadoses not advisable (toxicity effects)
• Mixed results in cancer‐vitamin A studies (most showing increased cancer risk in lung cancer prevention studies)
• Foods (not supplements) rich in vitamin A and other phytochemicals are advised
• The carotenoid lycopene (e.g. in tomatoes) may protect against prostate cancer but it needs to be processed and heated to activate lycopenes. 

Hypercarotenaemia

• High amounts of carotenoids in the bloodstream turns skin and eye’s a yellow‐orange colour
• High consumption of carrots/squash/betacarotene supplements (~ 3 carrots/day for an extended period)
• Can promote cancer, especially when combined with alcohol in smokers (abnormal oxidation products of beta‐carotene)

Sources of Vitamin A

Preformed

• Liver, fish oils, fortified milk, eggs
• Contributes to half of the average vitamin A intake

Proformed

Dark‐green leafy vegetables, yellow‐orange vegetables/fruits

Vitamin D

Two sources:

1. Dietary (20%~ of Intake)

• Vitamin D2 from plants (ergocalciferol)
• Vitamin D3 from animals (cholecalciferol)

2. Endogenous (80%~ of Intake)

• 7‐dehydrocholesterol as the precursor (in the skin) converted to vitamin D3 via UVB sunlight required for activation
• Liver and kidney involved in conversion to active form

Functions of Vitamin D

Regulates blood calcium and phosphate levels by:

1. Increases calcium absorption (by activating synthesis of calbindin)
2. Mobilisation of calcium from bones (Vit D allows CA to be mobilised from our bones)
3. Reduced calcium excretion (Vit can ↑ calcium reabsorption in the kidneys by reducing CA excretion)

Calcitriol (hormonally active metobolite of Vit D) creates a supersaturated Ca and P solution by ↑ osteoclast activity (breaks down bone) which allows bone re‐mineralisation

Calcium Regulation by PTH

• Parathyroid hormone (PTH): principal regulator of extracellular calcium
• PTH acts on bone, kidney and intestine through ↑ vitamin D action on the intestine
• PTH is activated by ↓ in blood calcium that ↑ conversion of 25‐OH(hydroxy)‐D3 (INACTIVE FORM) to 1,25‐(OH)2 (di-hydroxy)‐D3 (calcitriol) (ACTIVE FORM)
• ↓ Blood calcium = ↑ PTH = ↑ osteoclast activity
  • Osteoclasts promote bone demineralisation  which allows an increase in serum CA that aids every muscle contraction BUT at the expense of bone demineralisation 

Vitamin D Metabolism

We want to maintain serum CA and P stores which enables more efficient metabolic health, bone health and neuromuscular functions.

• Vit D3 and D2 go to the liver which produces 25-hydroxy-Vit D (OH)
• Kidneys convert 25-hydroxy(OH)D to the active form which is 1,25(OH) di-hydroxy-Vit D (calcitriol)
• If we have low serum CA calictriol acts on PTH to IN CA absorption from the intestine and mobilise CA stores from bone which IN serum CA 

Osteoclasts, Osteoblasts & Osteocytes

Bone Health: Role of Calcitonin

Antagonist to Calcitriol

Increased blood calcium leads to decreased parathyroid hormone which leads to decreased osteoclast activity.

1. Secretion (by thyroid gland) stimulated by high blood calcium
2. Lowers blood calcium
3. Slows down the rate of vitamin D (calcitriol) activation
4. Protects against excessive bone resorption by inhibiting activity of bone‐resorbing cells (osteoclasts)

Vitamin D Deficiency

• Presents as ↓ 25(OH)D an ↑ PTH and potenally ↓ Ca and P
• 30 ‐ 50 nmol/L 25(OH)D (mild deficiency) associated with ↑ body
  sway which increases falls risk
• < 30 nmol/L 25(OH)D associated with ↓ muscle strength
• Deficiency presents with myalgias, proximal myopathy and muscle weakness and ↓BMD
• Endemic in institutionalised elderly residents, dark skinned people
  in more northerly or southerly latitudes, and veiled women
• We measure 25OH because we have lots more of it and we only have small amounts of 1,25OH.

Rickets: Low vitamin D in children (requires both lack of exposure to sunlight and a poor diet)

• ↓ calcification of growing ends of bones (epiphyses)
• Bones bow under pressure. Could that be why I have bowed legs?
• Seen in cystic fibrosis (fat malabsorption)

Osteomalacia: (soft bone) adult form of rickets

• Due to dietary vitamin D deficiency, lack of sunlight or to extensive liver or kidney damag
• Less obvious symptoms compared to children

Food Sources of Vitamin D

>80% of vitamin D in Australia/NZ comes from sun exposure

Limited range of foods:

• Oily fish (salmon, herring)
• Egg yolks
• Liver
• Margarine in Australia is fortified

Vitamin D Toxicity

• Regular intake of 80‐125 x AI (Adequate Intake) can be toxic
• From excess supplementation (not from sun exposure)
• Symptoms: over‐absorption of calcium (hypercalcaemia), increased calcium excretion
• Calcification of soft tissues as calcium deposits in kidneys, heart, and blood vessels
• Mental retardation in infants
• THIS IS WHY K2 IS TAKEN WITH VIT D

Vitamin E

8 naturally occurring forms ‐ includes tocopherols and tocotrienols

• Most important form is α‐tocopherol
• Amount absorbed is dependent on fat intake
• Transported via chylomicrons to the liver
• Transported via VLDL, LDL, HDL from the liver
• Found concentrated in areas where fat is found – liver, brain, adipose tissue
• Main action is as an antioxidant to reduce the risk of oxidation and damage to fatty acids
• Vit E is part of the lipid bi-layer of cells
• Most of the body’s vitamin E is found in plasma membranes

Food Sources of Vitamin E

• Plant oils
  • The more Vit E in oils the greater it’s shelf life
• Wheat germ
• Sweet potato
• Peanuts
• Margarine
• Nuts and seeds

Redox Agent (Transfer of Electrons)

• Vitamin E is able to donate an electron to oxidising agents (free radicals = unpaired electrons) to neutralise the free radicals
• Because of this Vit E protects PUFAs within the cell membrane and plasma lipoproteins
• It prevents the alteration of cell DNA and therefore potential risk of cancer development

Vitamin E as an Antioxidant

Free Radicals

FR aren’t all bad they can be involved in our immune system.

• Production of FR’s is a normal result of cell metabolism and immune function
• Involved in the natural destructive to cells (apoptosis): sets off a chain reaction
• Results in lipid peroxidation (oxidative degradation of lipids. It is the process in which free radicals “steal” electrons from the lipids in cell membranes, resulting in cell damage)

Form and accumulate in our bodies as a result of:

• Cigarette smoke
• Air pollutants such as ozone and nitrogen dioxide
• Some food preservatives, including nitrites
• Aerobic activity
• Metabolism of fats

Free Radicals Oxidise

Free radicals contain an unpaired electron.

They damage:

• Nucleic acids ‐ leading to cancerous changes
• Lipids, including those in membranes, and LDL in arteries
• Enzymes which repair cell structures
• Other proteins, including collagen in skin

Antioxidant Defence System

Vitamin E: interaction with lipid radicals

Vitamin C

• High reactivity with oxygen‐centred radicals
• Converts to dehydroascorbic acid and in turn converted back to ascorbic acid
  via glutathione
• Helps regenerate vitamin E

Glutathione

• Glutathione peroxidase (contains selenium) oxidises glutathione (GSH) to glutathione disulphide (GSSG) using a hydroxy radical.
• GSSG is regenerated back to GSH by glutathione reductase (contains
  selenium) which requires NADPH
• Lessen the burden of vitamin E because we don’t want Vit E doing all the work

Summary: In the lipid bi-layer we have Vit E being regenerated from it’s oxidised form to its reduced form via interaction with Vit C so it can continue working as a antioxident.

Antioxidants & CVD

• Observational studies show diets high in antioxidants linked to lower rates of CVD
• RCTs with supplements don’t show such benefit
• Meta‐analysis from 2013* involving 50 RCTs concluded that antioxidant supplements don’t prevent CVD (CI = 0.98-1.02)
• Probably doesn’t because our antioxident defence system doesn’t just rely on one player it relies on a whole complex system.
• Agrees with similar research showing lack of benefit in reducing cancer risk

* Myung S-K et al. Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and metaanalysis of randomised controlled trials. British Medical Journal Epub online January 18, 2013. doi: 10.1136/bmj.f10

Vitamin E Supplements & Mortality

• Review of 19 trials (130,000 people) involving vitamin E supplementation to prevent or manage various diseases showed GREATER mortality risk
• Dose‐response effect of vitamin E on all‐cause mortality
• 400 IU/day (~200 mg/day): 10% higher mortality than placebo
• Megadoses of 2,000 IU/day (1,000 mg/day): 20% greater risk of dying

AI (Adequate Intake) for vitamin E in Australia is 10 mg/day for adult males

Miller ER et al. Meta-analysis: high-dosage vitamin E supplementation may
increase all-cause mortality. Annals of Internal Medicine 2005;142:37-46

The More the Better?

• Vitamin E is only one of many antioxidants
• Likely that a combination of antioxidants is more effective
• Inhibits LDL oxidation (?? heart disease protection)
• Diversify your antioxidant intake with a balanced and varied diet
• Megadoses of one antioxidant may interfere with the action/absorption of another

Vitamin E Deficiency

Primary deficiency due to inadequate intake is rare (long‐term low‐fat diets, malabsorption syndromes)

Causes erythrocyte haemolysis (from membrane damage) because Vit E helps protect the membrane of RBCs especially. If there isn’t enough Vit E cell membranes can rupture leading to a loss of RBCs and hemoglobin leading to aneamia.

• Premature infants at risk
• Haemolytic anaemia can be treated with vitamin E

Vitamin E Recommendations

Vitamin E Toxicity: Rare and the least toxic of the fat‐soluble vitamin

• Upper level for adults: 300 mg/day
• May augment the effects of anticlotting medication

Vitamin E Recommendations

• RDI men: 10 mg/day
• RDI women: 7 mg/day

Vitamin K (“Koagulation”)

Scandivien spelling from it’s original discovery. 

Types of Vit K:

Phylloquinone (K1 from plants)

Menaquinone (K2; synthesised by bacteria)

• 40%‐80% of dietary viamin K is absorbed
• Absorption requires bile and pancreatic enzymes
• Role in the coagulation process
• Has calcium‐binding potential: involved in formation of osteocalcin (binds calcium; involved in bone formation)

Blood Clotting

• Vitamin K essential for formation of prothrombin and at least 5 other clotting factors (factors VII, IX, X, and proteins C and S)
  • prothrombin time = a measurement of blood clotting speed
• Vitamin K acts as cofactor in y‐carboxyglutamate (part of osteocalcin and several blood clotting proteins) synthesis by adding CO2 to glutamate
• y‐carboxyglutamate residues strongly bind to calcium which is essential for the clotting process and bone formation

Blood Clotting Process

A Vit K deficiency will impede this whole blood clotting process 

Drugs & Vitamin K

When on certain anticaogulant drugs (excess bleeding) there needs to be careful monitoring of Vit K because anticaogulants are meant to stop the blood from coagulatting and Vit K will assist the blood to coagulate to help restore normal blood clotting. 

Now if the person is taking them to reduce heart attack and stroke then taking Vit K may reduce the efficacy of minimising blood clotting in the heart and brain?

Anticoagulants (e.g. Warfarin)

• Lessens vitamin K reactivation
• Lessens blood clotting process
• Need to monitor vitamin K intake as can counteract anticoagulant
  action

Antibiotics

• Destroy intestinal bacteria
• Inhibits vitamin K synthesis and absorption
• Potential for excessive bleeding

Deficiency of Vitamin K

• Characterised by bleeding disorders (from low prothrombin activity)
• Newborns at risk of haemorrhagic disease due to low vitamin K levels (because poorly transported Vit K across placenta) and sterile gut (no bacteria to produce Vitamin K during infancy)
• Seen in malabsorption syndromes and obstructive jaundice (limited bile secretion because something is blocking its secretion)
• Also seen with long‐term antibiotic use because of it’s affect on destroying gut bacteria

Food Sources of Vitamin K

• Liver
• Green leafy vegetables
• Broccoli
• Peas
• Green beans
• Resistant to cooking losses
• Limited vitamin K stored in the body
• Toxicity unlikely (readily excreted)

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The Key Minerals

Week 10

Calcium

The most abundant mineral in the body. 1.9% of body weight (1.5kg in a 80kg body).

Distribution of Calcium in the Body:

• 99% in bones
• 0.5% in teeth
• 0.5% in soft tissues (i.e. skeletal muscle)
• 0.03% in plasma (drive bone growth, enable muscle contractions and blood clotting)
• 0.06% in interstitial fluid

Calcium Metbolism Summary

Functions of Calcium

1. Bone Structure and Strength

• Calcium salts (hydroxyapatite – Ca10(PO4)OH2 embedded in collagen fibers.
• Metaphore: collagen are the metal bars and hydroxyapatite is the cement.

2. Blood Clotting

Participates in several steps of the clotting process (prothrombin -> thrombin that allows clotting)

3. Nerve Transmission

Action potential at a synapse stimulates calcium influx -> releases neurotransmitter (ACh)

4. Muscle Contraction

• Nerve impulse releases calcium from intracellular stores
• Interacts with actin and myosin
• This is why low serum CA causes Tetany is a symptom that involves overly stimulated neuromuscular activity. It often leads to muscle cramps and contractions.

5. Hormonal Signals

• Many hormones act via calmodulin
• Calcium binds to calmodulin triggering enzyme action in metabolism, inflammation, immune responses, and muscle contraction

Calcium Absorption

• Adult absorption varies from 20 to 40% of food intake
• Absorption process is both passive and active (regulated by vitamin D through calbindin)
• Absorption affected by age (highest absorption during growth and pregnancy, lowest rate of absorbtion post‐menopausal)

Enhances CA Absoprtion:

• Acidic environment in gut
  • Means older people tend to absorb less CA because of their lower ability to produce HCL
• Vitamin D
  • Regulated through calbindin
• Glucose and lactose
• Intestinal movement
• Phosphorus (not high levels)

Decrease CA Absorption

• Dietary fibre
  • Bind to CA and get excreted
• Oxalates
  • Bind to CA and get excreted
• High phosphorus
• Caffeine

Calcium Regulation

Important role of vitamin D (Calcitriol)

1. Increases calcium gut absorption
2. Increases calcium release from bones
3. Increases kidney reabsorption (↓ in CA losses)

Regulation of blood calcium (critical) kept between 2.25 ‐2.60 mmol/l

Estrogen: ↑ synthesis and effectiveness of calcitriol action
on bone which is why during menapause low E leads to less CA absorption and implies poorer bone health and osteoporsis/arthritis because of increased osteoclast activity that promote bone demineralisation

Parathyroid hormone (PTH):

• principal regulator of extracellular calcium
• PTH acts on bone, kidney and intestine (↑ vitamin D action on intestine)
• PTH actvated by↓ blood calcium to ↑ conversion of 25‐OH‐D3 to 1,25‐(OH)2‐D3 (calcitriol)
• ↓ Blood calcium = ↑ PTH = ↑ osteoclast activity that promote bone demineralisation

Bone Health

Bone health needed for:

• Structural integrity of the skeleton (undergoes continuous remodelling and renewal)
• Response to needs for [Ca+] in extracellular fluid (bone acts as a reservoir for CA)
• 1/3 of bone is matrix collagen (support structure)
• 2/3 of bone highly ordered hydroxyapatite (bone mineral)

Low Calcium Intake

Low dietary intake (300-400mg p/d) → no effect on plasma levels, but may result in bone loss

Osteoporosis

• ↓bone density through life leading to bone fractures (risk ↑ with age)
• Loss of bone accelerates around menopause in women
• Protection by ensuring highest peak bone mass (PBM) in late adolescence via weight bearing activity
• PBM strongly influenced by genetics

• Peak bone mass around 35-40
• Adolescene period massively influences peak bone mass potential which is why mechanical loading and adequate CA intake is critically important during adolescence 
• 0.5-1%% loss of bone mass per year past 50’s. Accelerated for women 2-3% per year at the onset of menopasue 

Osteoporosis

Factors promoting:

1. Low physical activity (especially weight‐bearing exercise)
2. Low dietary calcium
3. Declining vitamin D with age
4. Loss of sex steroids like E (osteoblasts and kidneys have estrogen
receptors)
5. Smoking (↓ estrogen), alcohol (↓ estrogen, ↑ PTH, and ↓ Ca absorption) and salt (↑ PTH)

Calcium ± Vitamin D: Effects on Fractures

Foods Sources of Calcium

Note: Spinach CA bioavailbility is lower during to oxalte content in spinach however heating spinach can decrease oxalate content dramtically. 

Phosphorus

• Second most abundant mineral in the body after calcium (~ 1% of body weight)
• Found mainly in bones and teeth (85%), but also in body fluids
• Absorption improved by vitamin D (calcitriol) and presence of calcium

Roles of Phosphorus

• Essential for bone health (part of hydroxyapatite)
• Involved in virtually all biochemical reactions via ATP
• Involved in phosphorylation of enzymes e.g. insulin receptor
• Part of DNA and RNA
• Involved in acid/base balance of the body (a differing factor from CA)
• Part of Phospholipids in cell membrane

Food Sources of Phosphorus

• Dairy products (half of intake)
• Meat
• Dried fruit especially
• Eggs
• Cereals
• Soft drinks are a source of phosphorus

Excess may contribute to low bone mass by displacing Ca from the diet and potentially ↑  Ca loss from bones (P ↑ PTH production and results in ↑ P loss from kidneys)

Phosphate Deficiency/Toxicity

• ↑ plasma P with muscle and bone catabolism
• Toxicity (hyperphosphataemia): Caused by renal disease, hypoparathyroidism, acute muscle breakdown
• Results in Ca‐P precipitates and organ damage
• Deficiency (hypophosphatemia): Usually secondary to other diseases e.g. refeeding syndrome after extended fasting, GI malabsorption, starvation, alcoholism
• Results in rickets/osteomalacia, bone pain, muscle weakness, anorexia (loss of apetite), cardiac arrhythmias and even death

Magnesium

• Most abundant in bones
• Around 60% in complex with phosphates
• 1% is in extracellular fluid: carefully regulated by kidney reabsorption
• Factors affecting body content: calcium (‐), phytates (‐), protein content of diet (+), alcohol (‐)

Role of Magnesium

• Cofactor in over 300 enzymes in the body – really important in regulator of homestatis of other minerals such as phospherus and CA
• Cofactor in the formation and transfer of high‐energy phosphate groups (inferring a relationship with ATP)
• ATP reacts as a complex with Mg
• Involved in DNA and RNA synthesis
• Muscle contraction
• Parallels calcium and phosphate
• Interplay between calcium and phosphate in muscle contraction

Dietary sources of Magnesium

• Vegetables, nuts, cereals, seafood
• Dairy not a rich source (unlike calcium and phosphorus)
• Deficiency: Not seen in humans eating a normal diet. Occurs in: alcoholics, renal disease, malabsorption syndromes
• Effects: nervous and muscular problems, cardiac arrhythmias

Iron

• Found in small amounts in every cell
• only about 15% of ingested iron is absorbed. 
• Most of the iron in our body is in the form of either haemoglobin (carried in blood) or myoglobin (carried in muscle), both proteins, that have oxygen carrying capacity. 

Haem (haemoglobin and myoglobin) iron vs Non‐haem iron

• Haem iron found in animal foods is better absorbed than nonhaem
• Non-haem iron is found in both plant and animal foods
• Approximately 25% of haem and 17% of non-haem are absorbed
• Ferrous iron (animal) (Fe2+) is better absorbed than Ferric iron (plant) (Fe3+)

• Ferrous is better absorbed (ferric is virtually insoluble) but Vitamin C enhances absorption by converting ferric Fe to ferrous Fe (vitamin C is thus ‘oxidised’)
  • But Vit C doesn’t enhance absorption from meat sources (ferrous iron) it only has an impact on converting non-animal iron into the ferrous form

Functions of Iron

• Haemoglobin in red blood cells
  • Transport oxygen and carbon dioxide
  • High turnover, high demand for iron because constant respiration
  • Half life of haemologlobin = 50 days
• Myoglobin in muscle cells (acts as an oxygen reservoir)
• Involved in Electron transport chain (used by cytochromes): iron acts as an electron carrier
• Enzyme cofactor for collagen synthesis and neurotransmitters
• Immune function
  • People who are iron deficient have a tendency to catch colf/flu symptoms more often
• Drug‐detoxification 24 pathway (P450 system in liver)

Absorption of Iron

• Acid in the stomach promotes the conversion of Fe3+ (ferric) to Fe2+ (ferris)
  • Why the elderly are at a higher risk for Iron deficiency because them have lower HCL production
• Hindered by phytates, oxalates, high fibre, high calcium, polyphenols (e.g. tea) because they tend ot bind to minerals that are divalent cations (two positive charge minerals – mag, iron, CA)
  • High intake of these substances affect absorption
  • When you consume a plant based majority diet its going to impact iron absorption more so because you tend to consume more phytates, oxalaes, fibre and polyphenols from lots of plants which further decreases bioavailability of iron
• Iron absorption ↑ when body stores are low
• 18% absorbed from mixed diet, 10% from vegetarian diet largely due to heme and non-heme differences 
  • But a 8% difference is relatively a small amount. But the health implications can be dramatic over long term.
  • Vegetariens need ~1.8-2.0x the amount of iron in their diet due to lower iron aborpstion amounts
• 5‐35% haem and 2‐20% non‐haem iron absorbed

Iron Absorption

Increases Absorption

• Haem iron in food increases non-haem iron from plant sources
• Vitamin C
• Animal protein
• Low iron stores
• HCL (alters solubility)
• MFP factor enhances absorption of non-heme iron (a peptide found in protein in meat, fish, and poultry)
• Iron in breast milk (lactoferrin)
  • Iron in baby formula is much higher than breast milk because formula iron is much less bioavailable

Decreases Absorption

• Phytates (cereals, legumes, nuts)
• Oxalates (in leafy vegetables)
• Excess of Zn, Ca, Mn tends to displace iron absorption
  • Practical implications to not take Zn, Mn, Ca supplements or mineral rich meals like dairy with iron rich meals. This is why we recommend taking certain supplements 1-2h away from food to minimise competing absorption.
• High iron stores
• Decreased HCL production
• Polyphenols (tea, coffee, red wine)

Storage of Iron

Transferrin carries iron in the blood. Some iron is delivered to in myoglobin in muscle cells. Bone marrow incorporates iron into haemoglobin of red blood cells and stores excess iron in ferritin.The liver and spleen dismantle red blood cells and packages iron into transferrin as well as storing excess iron in ferritin.

Ferritin: In the intestinal cells and tissues (mostly liver) for short‐term storage.

Transferrin: major blood transporter of iron

Haemosiderin: insoluble iron storage protein in the liver (to deal with iron overload). E.G. With haemochromatosis.

• As iron stores increase, transferrin is saturated and as a result iron absorption decreased
• Storage: 70% in RBCs and myoglobin (in muscle) and the rest in liver, bone marrow, and spleen
• No method for excretion except for blood loss, gut losses, and in pregnancy

Iron Absorption

Excess iron is stored in the mucosal ferritin which is a storage protein. If the body doesn’t need iron then it is not absorbed but instead excreted in shed intestinal cells. If the body does need iron then mucosal ferritin releases iron to mucosal transferrin, a type of transport protein. Iron is transported around the body for use (most of the iron in the body is recycled) 

1. Iron transported accross the intestinal cells bound to transferrin (iron transporter)
2. Delivered to muscles in the form of myoglobin
3. Stores in bone barrow, liver and spleen
4. Majority of iron is in circulating RBCs
5. Some iron is lost through GI tract (sloughed off) and the breakdown of RBCs
6. Majorty of iron is recyclable

Iron‐Deficiency Anaemia

• Most common form of anaemia
• ↓ levels of haemoglobin and haematocrit (RBC volume) leads to ↓ production of RBCs and oxygen capacity
• Symptoms: Paleness, brittle nails, fatigue, difficulty breathing, poor growth, impaired cognition, reduced immune function and developmental milestone delays
• Infants and babies who are iron deficient are often given way too much milk formula so they have no appetite for most other foods. Milk is a poor source of iron so decreasing milk intake from high to normal can be a useful dietery intervention to regain hunger for iron rich foods.

Causes of Iron Deficiency

Stages of Iron Deficiency

1. Iron stores diminish (↓ in ferritin‐bound iron) (a-symptomatic)
2. Transport iron ↓(↓ in % transferrin saturation) (symptomatic)
3. Haemoglobin production ↓ (symptomatic)

Treatment

• Medicinal forms of iron supplements e.g. ferrous  sulphate
• Well‐balanced diet
• Possible intravenous or intra‐muscular iron if oral iron is poorly absorbed

Food Sources of Iron

• Red meat ~ 2 mg/100 g
• Chicken ~ 0.5 mg/100 g
• Fish ~ 0.3 mg/100 g
• Enriched grains
• Fortified cereals (especially infant cereals)
• Green, leafy vegetables (Vit C to enhacne absorption)
• Milk is a poor source

RDIs for Iron

• 8 mg/day for adult males and post‐menopausal females
• 18 mg/day for pre‐menopausal females (average female getting regular cycle)
• 27 mg/day in pregnancy

 

• Vegetarians need ~1.8‐times RDI to allow for lower bioavailability
• Blood loss is ~5 mg Fe/10 ml (therefore menstrual loss is ~15 mg iron/cycle)
• Total body storage is ~3‐4 g

Toxicity of Iron

• Can be serious, especially for children (especially via supplement overdoses)
• Diarrhoea, constipation, nausea, abdominal pain (common symptom of taking iron supplements)
• Upper level is 45 mg/day
• Causes death due to respiratory collapse (shock)

Haemochromatosis

• Recessive genetic disease
• Over‐absorb iron: iron deposits which can lead to organ damage, diabetes, heart disease, and arthritis
• May go undetected until 50‐60 y.o. when organ fails
• Treatment by frequent ‘bleeding’

Zinc

• Cofactor to many enzymes
• Synthesis of nucleic acids
• Wound healing, immune function (WBC production), growth
• Blood clotting
• Reproductive growth: Development of sexual organs and bones
• Insulin function

Absorption of Zinc

• Transported in blood by albumin and transferrin
• Absorption increases with low intakes

Metallothionein binds and regulates the release of zinc in intestinal cells (mucosal block works against overabsorption of zinc which gets activated once zinc levels have reacher needed threshold)

Decreases Absorption:

• Presence of phytates decrease absorption
• Calcium supplements decrease zinc absorption
• Competes with copper and iron absorption

Deficiency of Zinc

• Poor growth
• Inadequate sexual development
• Reduced sense of smell and taste
• Delayed wound healing
• Mental confusion
• Hair loss
• Lack of appetite
• Impaired pancreatic function

Who is at Risk for Zinc Deficiency?

• Hospital patients with malabsorption
• Protein‐energy malnutrition
• Sickle cell disease (need increased zinc needs due to RBC loss)
• Alcoholics, anorexia nervosa, elderly, pregnant, vegans

Toxicity of Zinc

• RDI: 10mg /day
• Upper limit is 40 mg/day
• Inhibits copper absorption (increased metallothionein – binds more copper)
• decreased HDL, increased LDL ‐ increases risk of heart disease
• Diarrhoea, cramps, nausea, vomiting
• Depressed immune function

Food Sources of Zinc

• Meat and poultry
• Shell fish
• Dairy foods
• Legumes

Iodine

• Involved in the synthesis of thyroid hormones (T3 and T4)
• T4 is converted to T3 (active hormone) regulating BMR

T3 regulates:

• Basal metabolic rate
• Production of body heat energy
• Growth
• Reproduction
• CNS development

Deficiency of Iodine

• Growth of the thyroid gland (goitre)
• Drop in metabolic rate
• Harmful during pregnancy (results in cretinism – mental retardation)
• Consumption of goitrogens (raw turnips, cabbage, Brussels sprouts, cauliflower, broccoli) which inhibits iodide metabolism – but when you cook those foods those goitrogens are inactivated by heat

Food Sources of Iodine

• Iodised salt (now used in bread making)
• Saltwater fish, seafood
• Plant source dependent on soil content (low soil iodine in Tasmania)
• Milk ‘contaminated’ with iodine from use of sanitisers

Iodine Deficiency in Australia

↓ iodine intake in Australia from less use in dairy industry and ↓ iodised salt

• National Iodine Survey* found evidence for borderline deficiency in sample of school children (esp. Victoria and NSW)
• Concern that findings also relate to pregnant mothers

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Water & Electrolytes

Week 11

Water Compartments

• Comprises 50‐70% of the body by weight
  • Intracellular fluid (2/3 of pool) (fluid within the cell)
  • Extracellular fluid (1/3 of pool)
• Interstitial (fluid between cells)
• Intracellular (fluid within the cell)
• Intravascular (blood stream and lymph)

Functions of Water

• Metabolic processes
• Water acts as a universal solvent for minerals, vitamins, amino acids, glucose and
  others where those substances can disolve in
• Body temperature regulation
• Water absorbs excess heat
• Body secretes fluids via perspiration (evaporative heat loss) – skin is cooled as perspiration evaporates
• Removal of body waste via urine/faecus
• Part of the amniotic fluid, joint lubricants, saliva, bile
• Blood transport

Fluid Balance

Water and fluid balance is controlled by the electrolyte concentration of certain cells

“Where ions go, water follows” Which is why high NA intake stimulutes more urine production.

Regulation of fluid, electrolyte and acid-base balance depends primarily on the kidneys

Osmalarity

Concentration of a solution

Osmosis

Movement of water from a less concentrated to a more concentrated solution

Osmotic pressure

Amount of force applied by water necessary to prevent the dilution of osmolites

Water Balance

Water Input

• Drinking 1 Litre
• Water content of foods 1 Litre
  • *why the quality of water you use (tap or filtered) matters when cooking because the foods abosrb the water.
• Metabolic synthesis 300 mL

Water losses

• Urine Minimum of 500 mL
• Skin (perspiration) 500 mL
• Lung 400 mL (respiration and talking)
• Faecal 150 mL

Regulation of Water Balance

1. Thirst

Relatively insensitive: about 2% of the body’s fluid must be lost before activation of the thirst response

Responses

• Conscious feeling of thirst (via hypothalamus) = main role of the hypothalamus in regulation of water balance
• Activation of posterior pituitary gland to secrete antidiuretic hormone (a.k.a. ADH or vasopression)

2. Output

Fall in blood volume and blood pressure (due to dehydration)

ADH causes vasoconstricon (↑ blood pressure) and ↑ permeability of the distal and collectng tubules in the kidney to water to we can reabsorb more water

*ADH inhibited by alcohol and caffeine which is why you urinate so freqeuntly when drinking

Renin‐Angiotensin System (RAS)

Involved in blood pressure regulation

1. Kidney secretes renin (enzyme) ‐ signalled by baroreceptors via a change in blood pressure

(Renin is a key proteolytic enzyme produced by the kidneys involved in water balance)

1. Renin converts circulating angiotensinogen (via the liver) to form angiotensin I

2. Angiotensin I converted to angiotensin II in the lungs and kidneys (via angiotensin converting enzyme; ACE)

Hence why ACE inhibitors are used to control and decrease high blood pressure via the inhibition of the convertion of angitensin I to angiotensin II 

1. Angiotensin II (vasoconstrictor) promotes release of aldosterone

2. Aldosterone promotes sodium retention in the kidneys (which ↑ osmolarity and helps to retain water). That is why if we hold onto NA we’re going to hold onto fluid. (Hence why when people try and cut body weight they decrease NA intake).

Dehydration

• When we are dehyrated we have a decrease of volume in our ECF
• Water losses accentuated in hot climates, with exercise and in fever and illness (e.g. diarrhoea, burns)
• As ECF fluid is lost, osmolarity increases, and water is drawn from within cells to the ECF which leads to cell shrinkage 
  • Osmolarity increase means that electrolytes and the solute concentration increases and it is water that will move to try and disipate that concentration increase.

Symptoms

• 1‐2% body fluid loss: thirst, economy of movement, anorexia (loss of appetite), increased heart rate, nausea
• 3‐6 % body fluid loss: dizziness, headache, absence of saliva, inability to walk
• 7‐10% body fluid loss: delirium, swollen tongue, inability to swallow, deafness, dim vision, shrivelled skin

Toxicity of Water? Hypernatraemia

• Excess water without sufficient electrolyte intake overwhelms excretion capacity of kidneys → that dilutes ECF Na+ (hyponatraemia)
• ↓ Na+ → water moves from ECF to ICF → water enters brain → cerebral oedema
• Seen in some athletes (e.g. marathon runners, athletes trying to foil drug tests) renal disease, CHF (congestive heart failure), mental illness (psychogenic polydipsia)

Hyponatraemia Symptoms

Normal Serum [Na+]: 135 – 145 mmol/L

Serum [Na+] > 130 mmol/L – Usually asymptomatic

Serum [Na+] > 125‐130 mmol/L – GI symptoms (nausea vomiting)

Serum [Na+] < 125 mmol/L – Lethargy, headache, blurred vision, ataxia, psychosis

Cerebral oedema → seizures, coma, respiratory distress/arrest

Fluid & Electrolyte Distribution

• NA is our major electroyle in our ECF and the biggest driver of fluid balance in the body
• Electrolytes: Dissociate in water and exist as free, charged ions e.g. Na+, K+, Cl‐, P‐, Mg2+, Ca2+
• Concentration of electrolytes maintained by carriers and transport proteins
• Osmosis: Water moves from high water (low electrolyte) concentration to low water (high electrolyte) concentration

Sodium

• Principle positive ion (cation) in the extracellular fluid
• Aldosterone regulates sodium balance
• Key for retaining body water (maintains osmolarity)
  • Total osmolarity is 285 mmol/L
    • NA is about half of that total
    • total osmolarity = concentration of ALL electrolytes
  • In ECF, sodium is ~ 150 mmol/L
• Participates in nutrient absorption
• Creates an electrical potential charge
• Involved in muscle contractions and nerve impulses
• 75% of the sodium eaten has been added to food by manufacturers

Sodium Transport

• Cells need to maintain ECF concentration of Na+ of ~150 mmol/L (ICF concentration is ~10 mmol/L)
• To go against the concentration gradient requires an energy‐dependent carrier to maintain concentration gradient that allows us to transport. This is known as the Na/K ATPase pump

Sodium Content of the Body

• Changes in plasma sodium concentration occur due to shifts in water
• As plasma sodium concentration changes, water, NOT sodium, is lost or retained to maintain the balance
  • Short Term: Maintaence of NA regulated by water
  • Long Term: Body can regulate NA levels itself
• ECF volume needs to be greater than total extracellular Na+
• Important to maintain constant amount of Na+ in the body to keep constant ECF volume (related to blood pressure and cardiac output)

Sodium and the Kidneys

• 95‐99% of sodium is reabsorbed along the nephron  in response aldosterone
• Change in absorption much slower than response to ADH (water reabsorption)
• Whilst we reabsorb the majority of the NA the changing absorption rate is much slower over time in response to ADH

Changing from low to high Na+ diet results in:

1. Na+ excretion doesn’t rise rapidly the body will reabsorb more NA in the short term until the kidneys adapt to the chronic higher intake where it realises its receiving more NA than it needs
2. A transient period of positive Na+ balance occurs where we absorb more NA than what we need physiologically
3. That allows an increase in ECF volume and increase in body weight due to the fluid retension increase (where ions go water follows)
4. That results in an increase in blood pressure (some might have salt‐sensitive  hypertension where some peoples BP increases/decreases dramatically based on acute NA intake)

This process is quite slow and occurs over time. 

Salt & Hypertension

Hypertension (high blood pressure) defined as:

Systolic BP > 140 mmHg / Diastolic BP > 90 mmHg (greater predictor of disease)

• Risk factor for stroke, CHD, and renal failure because the kidneys are put under more strain due to the BP IN
• Populations with low sodium intake have lower BP
• Some segments of population are ‘salt sensitive’ – increases with age, related to family history
• BP also increased with obesity and alcohol (> 3 drinks/day)
• Salt restriction warranted in hypertensive people secondary to weight reduction, exercise and alcohol restriction

Deficiency of Sodium

• Rare
• Persistent vomiting/diarrhoea e.g. cholera
• Excessive perspiration (losing 2‐3% of body weight over the day/s)
• Sodium content of sweat is 50‐100 mmol/L (0.9-1.8g) and on average every 150 mmol (2.7g) of sodium lost ‘takes’ with it 1 L of water from ECF
  • This practically can infer how much NA you can lose per L of sweat. So for every L of sweat you lose 0.9-1.8g of NA which then infers a higher NA intake needed for those exercising frequently, especially in heat where they will lose high proportion of fluid/NA.
  • But  1 mmol Na+ = 23 mg Na+ = 58.5 mg NaCl (table salt) so my equation might be wrong
• Symptoms related to ↓ blood pressure and cell volume
• Muscle cramps, nausea, vomiting, dizziness, shock, coma
  • Experienced in Singapore during 36h fast.
• Normally kidney will respond by conserving sodium
• Treatment with saline (water + NA) as water alone will cause rapid cellular influx of water and swelling. Which is why when you rehydrate after long periods of fluid loss its critical to incoporate electrolytes into your rehydration, not just water along.

Food Sources of Sodium

• ~25% added ‘at the table’
• Most is added by food manufacturers in processed foods
• Bread
• Margarine/butter
• Processed meats
• Snack foods and take‐away foods

Sodium Needs

• Upper Level of Intake of 2300 mg (5.9 g NaCl (table salt) or 100 mmol of Na)
• Average intake is 2150 mg (35% of Australians consume above the UL)
• Adult needs are just 460‐920 mg/day
• 1 mmol Na+ = 23 mg Na+ = 58.5 mg NaCl (table salt)

Water Loss Consequencs During Exercise

With water loss during exercise, potential for:

Stage 1. Heat exhaustion: From blood volume depletion due to fluid loss

↑ body temperature due to inadequate cooling (sweating) especially in humid environments.

• Symptoms: Headache, dizziness, nausea, visual disturbances.
• Treatment: Cool environment, sponge with water, fluid replacement as tolerated

Stage 2. Heat cramps: Complication of heat exhaustion. From large water and salt losses but with only water replacement

Stage 3. Heatstroke: Potentially fatal. Elevated body temperature due to inability of body to adequately cool

• Symptoms: Nausea, confusion, poor co‐ordination, seizures, inability to sweat
• Treatment: Ice packs, medical help

Sports Drinks

Typical composition:

~ 6‐8% CHO (glucose, dextrins). Higher sugar content can cause GI distress (e.g. soft drinks are ~12% sugar and contain fructose – not performance enhancing)

~ 0.5 g/L sodium

• Electrolytes help CHO absorption and to replace electrolyte losses and maintain blood volume
• As sodium and glucose transported into intestinal cells, helps create osmotic differential to promote water absorption
• Cold drinks help promote gastric emptying faster than warm drinks
• Not required for <60 minutes exertion in normal ambient temperatures as water can suffice (glucose and electrolyte loss not an issue). Though higher ambie temp/humidity decreases that time.
• Carbohydrate replacement beneficial for endurance athletes during competition
• Taste advantage helps ensure hydration (but will contribute calories for those trying to lose weight)

Chloride (Cl-)

• Negative ion (anion) for the extracellular fluid
• Absorbed in the small intestine and colon
• Excreted through the kidneys
• Components of hydrochloric acid (HCl), immune response, nerve function
• Excess is excreted by the kidneys/perspiration
• Mostly obtained from salt consumption

Potassium

• Major positive ion (cation) in the intracellular fluid (~150 mmol/L)
  • Makes up half~ of the concentration of the ICF
• Controls cell volume and fluid balance
• Nerve impulse transmission (due to membrane potential)
• Involved in muscle contractions
• Involved in enzymes for glycolysis and electron transport are K+ dependent
• Associated with lowering blood pressure

Foods Sources of Potassium

• Found in fruits, vegetables, milk, grains, meats, dried beans – no large differences as found in ICF
  • Which explains the association with low BP because people tend to have a healthier diet
• Processed foods not as good a source (typically these foods higher in Na+ than K+)
• Typical intake is 2000‐3000 mg/day
• Excess potassium excreted by the kidneys

Potassium Deficiency (Hypokalaemia)

Seen in:

• Use of some diuretics (because K+ readily lost through kidneys with reabsorption)
• Alcoholics, eating disorders, laxative abuse
• Changes in acid‐base balance
• Symptoms: Loss of appetite, muscle cramps, confusion, constipation, irregular heart beat

Potassium Excess (Hyperkalaemia)

• Not dietary related except in renal failure (body unable to remove excess K+)
• Seen with excess supplement use
• Seen with acute tissue breakdown (e.g. crush injuries) as those types of injuries release K+ into ECF leading to the ↑ in ECF K+ which reduces membrane potential which can have a an effect on the rhythm and rate of conduction of cardiac impulse (arrhythmias). So a crush injury to the leg can result in a heart attack due to the K+ release which affects conduction of cardiac impulss.
• Both hypokalaemia and hyperkalaemia can result in cardiac arrhythmias

Refeeding Syndrome

• Chronic malnutrition and starvation (e.g. extended fasting) followed by recommencement of nutrition poses risks due to adverse metabolic consequences
• Upon eating (especially carbs) insulin rises causing a rapid glucose and electrolyte uptake. Because we’ve had this chornic starvation/malnutrition we have a high risk of electrolyte deficiencies, in particularly phosphorus seem’s to be most sensitive.
• With that rapid uptake of those minerals we have some extracellular shifts of those particuluar nutrients. Becaue of those shifts you often end up with hypokalemia, hypomagnesaemia, hypophophataemia, thiaminme deficiency and NA/water retention (oedema).

Symptoms:

• Muscle pain, respiratory muscle weakness and cardiac arrhythmias from low blood phosphoprus (because we need it for ATP production and cellular oxygen release)
• Risk of Wernicke’s encepalopathy due to decreased thiamin stores and increased utlisation upon refeeding
• Fluid retension due to increased NA

Refeeding Syndrom Risk

• Anorexia nercosa
• Alcoholics
• Protein energy malnutrition (<10% loss of body weight)
• Starvation for 7-10 days
• Massive weight lose in obese patients
• Significant vomiting/diarrhoea
• Post-operative patients