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Home , Specific dynamic action

Physiology week 22 -

Metabolism ‘amount of liberated per unit time’

Respiratory quotient ‘ratio in steady state of volume of carbon dioxide to volume of oxygen consumed per unit time’ 1.0 0.7 (extra oxygen is required for formation of ) 0.82 (average value) Approximate amount of CHO, fat, protein consumed any one time calculated from RQ and urinary N2 excretion RQ brain 0.97-0.99

Factors affecting metabolic rate Height, weight, surface area Gender and age Growth, reproduction, lactation, emotional state Circulating levels of and catecholamines Muscular exertion (increases 10-20 times) Sleep (decreases 10%) Body and environmental temperature (metabolic rate rises 14% for each degree rise in body temperature) Recent ingestion of (specific dynamic action (SDA) of food obligatory energy expenditure) Starvation (decreases 40%)

Basal metabolic rate Standardized metabolic rate in order to minimize variation - average male 2000kcal/day Determined at rest in a thermoneutral room, 12 hours after last meal

Carbohydrate metabolism Fate of ingested glucose 5% converted to glycogen in the liver 30-40% converted into fat 55-65% metabolized

Carbohydrate reserves 2500kcal total (112000kcal (45 times more) in fat and protein) 400g muscle glycogen; 100g liver glycogen; 20g extracellular glucose

Organ use of Brain utilises 70-80% of glucose at rest, red blood cells utilise most of the rest (resting muscle utilises fatty acids) During , and increased muscle uptake of glucose supplies extra energy

Intracellular metabolism Glucose phosphorylated to G6P inside cells (hexokinase, glucokinase) G6P polymerized to glycogen/catabolised via EmbdenMeyerhof path or hexose monophosphate shunt to pyruvate Pyruvate is converted to acteyl CoA then to ATP, carbon dioxide and water via cycle (only aerobic) In anaerobic conditions, pyruvate is converted to lactate which is converted back when oxygen becomes available Interconversions between CHO, protein and fat occur via this pathway though conversion fat to CHO is limited

Carbohydrate digestion and absorption Digestion Mouth Salivary alpha amylase - Optimal pH 6.7, inhibited by stomach acid Small intestine Pancreatic alpha amylase (plus salivary amylase) Oligosaccharidases (lactase, sucrase, maltase, dextrinase) in brush border, digest products of amylase digestion to glucose, fructose and galactose Final oligosaccharides: alpha-dextrins, maltotriose, maltose, trehalose, lactose, sucrose metabolised to hexoses (monosaccharides – galactose, fructose or glucose)

Absorption 2 phases – 1st into intestinal mucosal cell and 2 nd into interstitial fluid and so into capillaries and portal blood Glucose and galactose Most glucose and galactose is absorbed before terminal ileum by secondary active transport 1 Sodium dependent glucose transporter (SGLT 1 and 2) transports glucose into enterocyte (sodium passes down conc gradient then is actively transported out of cell) Low conc Na inhibits transport Facilitated diffusion into ICF by GLUT2 Maximum rate of glucose absorption 120g/h Fructose Transported by facilitated diffusion into enterocyte by GLUT5 and out of enterocyte by GLUT2 Ribose/deoxyribose Diffusion

Protein metabolism Essential amino acids Phenylalanine, , Leucine, Methionine, Valine, , Isoleucine, , Threonine function Absorbed amino acids and amino acids derived from body protein form pool that supplies most needs of body Amino acids are essential for Formation of body protein Formation of hormones, catecholamines, histamine, serotonin, melatonin, purine and pyramidines Formation of urinary sulphates Interconversions occur between amino acids and products of carbohydrate and fat metabolism and involve transfer, removal or addition of amino groups Oxidative deamination of amino acids forms keto acids and ammonia. Ammonia is converted to urea Synthesised from methionine, glycine and arginine. In skeletal muscle creatine is phosphorylated to phosphorylcreatine which is an important store of ATP Phosphorylcreatine is either utilised as an energy source or converted to creatinine. Rate of excretion is relatively constant Uric acid Formed by Breakdown of purines Direct synthesis from 5-PRPP and glutamine Uric acid filtered, 98% reabsorbed 80% of urinary uric acid is secreted Nitrogen balance Amount of nitrogen in the urine equals the amount of nitrogen in the

Digestion Stomach Pepsinogen 1 and 2 - Secreted by stomach converted to pepsins by hydrochloric acid Optimal pH 1.6-3.2, therefore action terminated in duodenum and jejunum (pH 6.5) Cleave bonds of amino acids Gelatinase Small intestine Pancreatic proteolytic Trypsin, Chymotrypsin, Elastase, Carboxypeptidase Mucosal proteolytic enzymes (brush border) Enteropeptidase, Aminopeptidase, Carboxypeptidase, Endopeptidase, Dipeptidase Intracellular peptidases (cytoplasm of muscosal cells) Some di and tri peptides are actively transported into the cell then hydrolysed

Absorption 2 phases 1st into intestinal mucosal cell 2nd into ICF and so into capillaries and portal blood Rapid absorption in duodenum and jejunum, slow in ileum (Infants also absorb IgA in the lower intestine) Amino acids At least 7 different transport systems 5 are secondary active transport mechanisms involving sodium Two involve chloride, Two are independent of sodium Di and tri peptides Active transport with hydrogen

Infants absorb more undigested protein – absorb more IgA – passive immunity, but more

2 Fat metabolism Biologically important - Fatty acids, Triglycerides, Phospholipids, Sterols

Enzymes required for the digestion of lipids Lingual lipase (Ebner’s Gland) – active in stomach on triglycerides Pancreatic lipase – requires colipase for maximal activity (triglycerides) Pancreatic bile-salt activated lipase (not trigs but also esters, some and phospholipids) Cholesteryl ester hydrolase (cholesterol)

Lipid absorption from GI tract 2 phases Into intestinal mucosal cell Into interstitial fluid (ECF) then into capillaries and portal blood (FFAs) or into lymphatics (chylomicrons)

Into enterocytes: passive diffusion and carriers Out of enterocytes: depends on size (<10-12 carbons – directly into portal blood – FFAs or >10-12 carbons – reesterified to trigs or chol esters and packages in chylomicrons – coating of protein, chol and phospholipids)

Other process involved in digestion of lipids Emulsification Micelles – formed from bile salts, lecithin, monoglycerides surrounding FAs, monoglycerides and cholesterol Transport lipids thru “unstirred layer” to brush border of muscosal cells

Fatty acid oxidation and synthesis Fatty acids broken down to acetylCoA that enters the and yields ATP, carbon dioxide and water. 1 mol of fatty acid generates 44 ATPs versus 38 produced by carbohydrate Fatty acids are a major source of energy for many tissues, especially the heart Fatty acids can be synthesized from acetylCoA in many tissues. In fat depots, fatty acids are combined with to form triglyceride.

Lipoprotein lipase and hormone sensitive lipase - 2 lipases regulate supply of FFAs Endothelial derived lipoprotein lipase Intracellular hormone-sensitive lipase Activity increased by Catecholamines, Growth hormone, Glucocorticoids, Thyroid hormones. Activity decreased by Insulin, Prostaglandin E

Ketone bodies Acetoacetate is formed from acetyl CoA in the liver, then converted to beta hydroxybutyrate and acetone These compounds are metabolized with difficulty in the liver therefore diffuse into the circulation Tissues other than the liver metabolise acetoacetate to carbon dioxide and water via the citric acid cycle. If acetylCoA accumulates (due to decr supply of products of glucose metabolism) and keto acids accumulate.

Lipid cells Lipids in cells are of 2 types Structural lipids Neutral fat - mobilized in starvation but structural lipid is preserved. Brown fat - small proportion (more abundant in infants) located between scapulae and at nape of neck. Contain many mitochondria and are responsible for ATP and heat production.

Plasma lipids and lipid transport Free fatty acids are bound to albumin. Cholesterol, TG and phospholipids are bound to lipoprotein complexes that increase the solubility of the lipids. Lipoproteins consist of a hydrophobic core of TG and cholesterol esters surrounded by phospholipids/apoproteins

Chylomicrons (APO C, E and B48) Formed in the intestinal mucosa during absorption of products of fat digestion Large lipoprotein complexes that enter the blood via lymphatics. Cleared from the blood by endothelial lipoprotein lipase (activated by apolipoprotein C-II) Lipoprotein lipase catalyses breakdown of TG to FFA and glycerol that then reenter adipose cells and are re-esterified or circulate in the blood bound to albumin Chylomicron remnants are internalized by liver cells and degraded.

3 VLDL (APO C, E and B100) Synthesised by the liver Transports TG formed from fatty acids and carbohydrates in the liver to extra hepatic tissues. Their TG is removed by endothelial lipoprotein lipase and they become IDL IDL (APO E and B100) IDL, formed by removal TG from VLDL, give up phospholipids, pick up cholesterol esters from HDL Lecitin-cholesterol acetyltransferase helps this process. Some IDL is taken up by liver. The rest of IDL loses more TG and protein and becomes LDL. LDL (APO B100) LDL is formed from IDL and supplies cholesterol to the tissues. Cholesterol is an essential component of cell membranes and hormones. LDL is recognised by its APO B100 component, binds to a receptor and is endocytosed. The LDL receptor is recycled and the endosome fuses with the lysosome where cholesterol is formed. HDL Cholesterol leaves as well as enters cells and is taken up by HDL HDL is synthesized in the liver and other tissues, transports cholesterol to liver where excreted in bile.

Cholesterol metabolism Cholesterol precursor of steroid hormones, component of cell membranes, absorbed from intestine, incorporated into chylomicrons - bring cholesterol to liver, where more cholesterol is synthesized. Some cholesterol is excreted in bile as a free form and incorporated into bile acids. Most cholesterol is incorporated into VLDL Cholesterol provides negative feedback by inhibiting further synthesis via inhibition of HMG CoA reductase. Plasma cholesterol is reduced by thyroid hormones and oestrogens; increased by diet and diabetes

Digestion Mouth Lingual lipase Secreted by Ebners gland on the dorsum of the tongue Active in the stomach. Digests up to 30% of dietary triglyceride Stomach Gastric lipase - Little importance Small intestine are emulsified by bile salts, lecithin and monoglycerides Pancreatic lipase Secreted as an inactive form and activated by trypsin Hydrolyses triglycerides to fatty acids and monoglycerides Pancreatic co-lipase Secreted as an inactive form and activated by trypsin Binds to lipase Bile salt activated lipase 4% of total lipase Catalyses hydrolysis of cholesterol esters, esters of fat-soluble vitamins, phospholipids, trigs Fatty acids, monoglycerides, cholesterol and bile salts spontaneously interact to form micelles that move down their concentration gradient to brush border of the enterocyte

Absorption Most absorption is in the upper parts of the small intestine. Passive (some evidence of carriers) transport into the enterocyte Fatty acids with less than 10-12 carbon atoms enter the portal blood and are transported as free fatty acids. Fatty acids with more than 12 carbons are re-esterified to TG and form chylomicrons

Absorption of water, sodium Water Input and secretions Ingested 2000ml Saliva 1500ml Reabsorption Stomach 2500ml Jejunum 5500ml Bile 500ml Ileum 2000ml Pancreas 1500ml Colon 1300ml Intestine 1000ml Total 8800ml Total 9000ml Water moves in or out of the intestine down its concentration gradient 4 Sodium Small intestine and colon Mostly passive diffusion down concentration gradient Active transport is important for co-transport of glucose and amino acids Basolateral membranes contain Na/K/2Cl transporters and chloride then secreted into lumen of intestine Basolateral membranes of enterocytes also contain sodium potassium ATPase. Increases in intracellular potassium result in diffusion down its concentration gradient into the lumen. Aldosterone increases the action of this

Iron 70% body iron in Hb, 3% in myoglobin, rest in ferritin Absorption As iron (bound) or free iron (non-heme) by different transport Heme iron absorption independent of pH Most ingested iron is ferric (3+) but more readily as Fe2+ - ferrous (soluble form) Minimal absorption in stomach but gastric acid dissolves iron, to form complexes with Vit C/other substances – converts it to ferrous form Most absorption in duodenum Iron actively transported across basolateral membrane into enterocytes via DMT1 Some stored as ferritin Rest transported out by ferroportin 1 in presence of hephaestin. In plasma oxidized to ferric, bind apotransferrin, form transferrin – normally 35% saturated Transported to portal circulation to liver then bone marrow Feedback alters rate of absorption.

Regulation of iron absorption Recent dietary intake of iron State of body iron stores State of erythropoeisis in bone marrow Absorption enhanced by C, Citric acid, Amino acids, Absorption inhibited by Tea, Carbonates, Oxalates, Phosphates Loss Lost from body from gut cells or menstruation

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