METABOLISM OF LIPIDS

1. METABOLISM OF LIPIDS

2. Things to know • How metabolic oxidation of lipids releases large quantities of energy through production of acetyl-CoA, NADH, and FADH2 • How lipids represent an even more efficient way of storing chemical energy

3. Introduction • Triacylglycerols – main storage form of lipids – bond between fatty acid and other molecules can be hydrolysed using lipases enzyme • Phosphoacylglycerols – membrane component – phospholipases • Spider/snake venom – phospholipases- tissue damage and rbc lysis- prevent clot formation

4. Release of fatty acids [2 Marks]

5. Fatty acid oxidation • Begin with activation of molecule • Thioester bond is formed between the carboxyl group of coenzyme A (CoA-SH) – by acyl-CoA synthethase (require ATP) • The activated form of fa – acyl-CoA

6. Β-oxidation • Fatty acids in the from of acyl-CoA molecules are broken down to generate acetyl-CoA, intermediate for TCA cycle • Involve 4 steps

7. For f.a with even number of carbon, the product is acetyl coa. • So for a 18C f.a – • 8 cycle • 9 AC • C18 – 1AC • C16 – 1AC • C14 – 1AC • C12 – 1AC • C10 – 1AC • C8 – 1AC • C6 – 1AC • C4 – 1AC • C2 – 1AC

8. B oxidation products TCA Cycle Final products 17 FADH2 + 35 NADH + 9 GTP = 148 ATP PER ONE

9. Comparison • One mole of glucose (6C) – Produce 36/38 ATP • 3mole of glucose (18C) – 108ATP/114ATP • One mole of f.a – 18C – Produce already 149 ATP!

10. They don’t need water • Metabolic water is produced during oxidation of f.a • Camel – lipid stored in humps • Kangaroo rats – diets of seed- rich lipid but no water – can live indefinitely without having to drink

11. Ketone bodies • Are produced when excess of acetyl CoA occur arises from B-oxidation • Occur when not enough OAA is available to enter TCA • Happen when organisms has high intake of lipid and low intake of carb in diets • Brain can metabolize ketone bodies (20% requirements)

13. Ketone bodies • Acetone can be detected in breath – ketosis • Ketone bodies acidic – their presence overwhelm the buffering capacity • Acetoacetate can be converted to acetyl-CoA to enter TCA • Ketonaemia- rise of ketone bodies in blood above normal level • Ketonuria – when blood level of ketone bodies rises above renal threshold, they are excreted in urine • Ketosis – accumulation of abnormal amount of ketone bodies in tissues and body fluid

14. Causes • starvation- simples form of ketosis occurs – due to depletion of carb reserve, coupled with mobilization of FFA and oxidation to produce energy • In pathologic states: in DM – clinical and experimental in some types of alkalosis – ketosis may occur pregancytoxaemia in sheep and lactating cattle 3. Non pathological states- high fat feeding and severe exercise in the postabsorbtive state

15. Ketosis • Ketosis can be abolished by increasing the metabolism of carb in diet • DM- give insulin • Ketogenic substances – ALL FFA • 40% of aa ketogenic • Antiketogenic – all carb, insulin, glucogenic aa, glycerol

16. CHOLESTEROL

17. Cholesterol • Membrane structure • Precursor for steroid hormones and bile acids

18. Biosynthesis of cholesterol • Cholesterol is synthesized in many tissues • Mainly in liver and intestine • Acetyl CoA is the precursor • More than half is synthesized in body • Remainder from diet

21. Cholesterol synthesis

22. Regulation of cholesterol synthesis • Is important to prevent accumulation and abnormal deposition of cholesterol in the body • Is primarily regulated by the enzyme HMG-CoAreductase • HMG-CoAreductase is inhibited by cholesterol itself • Fasting inhibit the enzyme – and activate the HMG-CoAlyase to form ketone bodies • The feeding of cholesterol reduces the hepatic biosynthesis of cholesterol • Cholesterol drugs: atorvastatin – inhibit HMG-CoaReductase

23. Hormonal effect • Insulin – increase HMG-CoA reductase actvity • Glucagon and glucocorticoid – decrease the enz activity • Thyroid hormones – stimulate the hormone activity

24. Other factors influence cholesterol level in blood • Dietary fats – diet in saturated fat increase cholesterol level • Dietary cholesterol • Dietary carbohydrates • Hereditity • Blood groups – higher in A and AB than O and B • Dietary fibers- cause excretion of cholesterol and bile acids in feces – reduce serum cholesterol • Exercise – lower cholesterol and increase HDL • Hypolipidaemic drug – block formation of cholesterol

25. Fate of cholesterol • Conversion to bile acids - excreted • Conversion to neutral sterols – excreted • Conversion 7-dehydrocholesterol – in skin, UV light will convert it to Vit D • Formation of adrenocorticol hormones • Formation of androgens, estrogens, progesterone

26. Lipid transport and storage • Fats from diets and lipids synthesized must be transported to tissues and organ – utilize and store • They are carried in blood plasma as plasma lipoproteins (macromolecular complexes of specific apolipoprotein) • Diff combination produce diff densities, chylomicrons <VLDL<LDL<HDL • Lipoproteins transport lipid from intestines as chylomicrons and from liver as VLDL to most tissues for oxidation and adipose tissuefor storage • Lipid is mobilized from tissue as free f.a

27. Types of apoproteins • HDL – apo-A-I and apo-A-II • LDL and LDL– apo-B100 • Chylomicrons – apoB48

28. Functions of apoprotein • Make the lipoprotein molecules water miscible (hydrophilic) • May acts as activator or inhibitor of specific enzymes. E.g • Apo-A-I and Apo-A-II act as LCAT activator • apo-C-I and C-II act as activator of lipoprotein lipase • apo-C-III- inhibitor of lipoprotein lipase • apo-B-100 and apo-E- bind with specific receptor on hepatic cells- lead to hepatic uptake

29. Synthesize of chylomicrons and VLDL • CM – in intestinal mucosal cells • VLDL – in liver • LDL- LDL is formed by degradation of VLDL (by losing some if its TG and apo) • Rich in cholesterol and cholesterol esters (bad cholesterol) – transport cholesterol to extrahepatic tissues • Cholesterol delivered by LDL to cells inhibit HMG-CoAreductase – inhibit cholesterol synthesize

30. Major fx • Chylomicrons • Carrier of exogenous TG. Transport mainly TG, PL, cholesterol ester and fat soluble vit from intestinal to liver and adipose tissues. Carrier for dietary lipids 2. VLDL • Carrier of endogenous TG – mainly transports TG synthesized in hepatic cells from the liver to extrahepatic tissues for storage 3. LDL • Transport and delivers cholesterol to extrahepatic tissues • Regulate cholesterol synthesis in extrahepatic tissues – cholesterol delivered by LDL to cells inhibit HMG-CoAreductase – rate limiting enzyme for cholesterol synthesis

31. Fate of LDL • LDL are taken into cell by endocytosis through receptor recognition • The presence of LDL receptor on the cell surface is important for uptake of LDL • LDL is hydrolysed to aa, cholesterol and fa • Free cholesterol – membrane component and inhibit the production of HMG-CoA reductase- suppressed synthesis of cholesterol – and also inhibit the synthesis of receptors – reduce intake of LDL. LDL level in blood increase – deposit as plaques

32. Fate of LDL • Cholesterol not needed for membrane can be stored as fatty acid ester – catalyzed by acyl-CoA : cholesterol acyltransferase (ACAT) • The presence of free cholesterol increases the enzymatic activity of ACAT

33. Catabolism • Lipoprotein lipases hydrolyzes TG from chylomicron to produce free fa and glycerol • The released fa are taken by cells • Lipoprotein lipases activity declines in adipocytes during starvation - reduce uptake of lipid by adipose tissue • Starvation enhances Lipoprotein lipases activity in cardiac and muscle – to oxidize more fa

34. HDL • Is synthesized in liver cells and in intestinal mucosa cells. Apo-A , Apo-E and Apo-C as the carrier • Strip off the cellular cholesterol from peripheral cells and muscles of arteries • Activates the LCAT- esterification of cholesterol to HDL • Transported to liver- catabolism

35. HDL • Provide Apo-C and Apo-E to VLVL and chylomicrons to be acted upon lipoprotein lipase • Stimulate synthesis of prostacylin synthesis by endothelial cells – inhibits platelet aggregation and prevent thrombus formation • Helps in removal macrophages from arterial wall

36. Bile acids • Bile helps in digestion and absorption of lipids • Stored in gallbladder • Bile acids -Steroid acids found in bileFx • Lowering surface tension – emulsification of fats • Accelerate the action of pancreatic lipase • Form micelles with fa-helps absorption • Aid in absorption of fat soluble vit

37. Bile acids • Keep cholesterol in solution • In GB, cholesterol is solubilized and held in micelles with the help of conjugated bile salts and phospholipids • Bile salts content decreased – imbalance of micelles- cholesterol leak out – crystallize and form gall stones • Gall stones – formed due to precipitation of cholesterol

38. Atherosclerosis • Excess LDLs invade tissues of the artery and become modified. The modified molecule stimulate the production of adhesion molecules, sticking out into the blood stream. Attract monocytes and T cells to the site. • Monocytes mature into active macrophages and produce many inflammatory molecules to digest LDL • Fat filled macrophages (foam cells) – earliest form of atherosclerotic plaque

39. Atherosclerosis • Inflammatory molecules promote growth of plaque and form a fibrous cap over the lipid core. The fibrous cap seal off the fatty core from the blood • Foam cells weaken the cap by secreting digesting matrix molecules. If the weakened cap ruptures, tissue factors display on the foam cells will interact with clot promoting element in the blood causing a clot (thrombus)

40. Familial cholesteralaemia – defective gene that code for receptor – develop atherosclerosis earlier

41. TASK • DISCUSS ON HYPERCHOLESTROLAEMIA IN ANIMAL – what animal involve? Due to what? Diet? Genetic defect? • Discuss on ketosis in animal – explain the mechanism • Discuss