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Lipid and Ketone Metabolism

Lipid and Ketone Metabolism

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Lipid and Ketone Metabolism

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  1. Lipid and Ketone Metabolism Week 12

  2. Lipids • Lipids: structure & function • Transport of lipids: albumin-binding & lipoprotein • Storage & release of lipids – adipose tissue • Catabolism: energy release from fatty acid • Activation of FA & carnitine shuttle • b oxidation of palmitic acid • Ketone bodies

  3. What are lipids? • Not soluble in water – man (or animal) is ~80% water • Soluble in organic solvents – acetone, ether • Saponifiable (can be split by hyrolysis) • Triglyceride (fats), waxes • Phospholipids, sphingolipids, glycolipids, lipoproteins • Non-saponifiable • Carotenoids, cholesterol, fat soluble vitamins (D, K, E, A)

  4. Functions of lipids • Fuel for energy metabolism • Membrane structure • Phospholipid, cholesterol • Hormone action • Steroids, prostaglandins • Electron transfer • Ubiquinone • Antioxidant • Vitamin E

  5. Importance of Lipid Metabolism • In health • Provision of energy in fasting/starvation • Provision of energy in pregnancy & for lactation • In diseases • Endocrine disease • Diabetes mellitus, Cushing’s syndrome • Production/metabolic diseases • Ketosis, pregnancy toxaemia, peri-parturient syndrome, fatty liver disease, hyperlipidaemia

  6. Linoleic, linolenic and arachidonic are essential fatty acids with >1 double bond • Important for membrane function • Cis double bond not trans

  7. Lipid of di-acyl glycerol provides the hydrophobic nature of phospholipid membrane

  8. Transport of lipid • Problem of solubility • From intestine – lipoprotein (chylomicrons) • From liver – very low density lipoprotein • From tissues to liver – high density lipoprotein • From adipose tissue – fatty acid binds to albumin

  9. Lipoproteins • Chylomicrons: • from intestine to adipose & other tissues • Very low density lipoprotein (VLDL) • TG, cholesterol ester & phospholipid to tissues • Low density lipoprotein (LDL) • Remnant of VLDL after release of lipid • High density lipoprotein (HDL) • Collects lipid, especially cholesterol for return to liver

  10. Lipoproteins: Central hydrophobic core of triglyceride, cholesterol ester Monolayer of phospholipid in outer surface, hydrophilic head to outer-face Apolipoprotein in phospholipid monolayer

  11. Lipoprotein composition (%)

  12. Apolipoprotein: Have many hydrophobic amino acids Hydrophilic amino acid on surface Provide structure Some have activity in lipid metabolism Apo A: predominantly in HDL, Cofactor for lecithin cholestrol acyl transferase (LCAT) Apo B :Predominantly in HDL & VLDL Apo C:Predominantly in HDL VLDL; Activates lipoprotein lipase in transfer of TG to adipose tissue Apo D:Predominantly in HDL Apo E: Predominantly in HDL & VLDL Apolipoproteins

  13. Fats in diet carried by chylomicron to tissues eg adipose Liver exports TG, CE PL in VLDL to tissues VLDL release lipids and become LDL LDL remnants to tissues and liver HDL is collecting lipid from tissues & from LDL to return to liver (reverse transport)

  14. HDL released from liver Collects excess cholesterol from tissues Produces cholesterol ester and lyso-lecithin from cholesterol and lecithin (phosphotidyl choline) Cholesterol ester to VLDL and TG from VLDL HDL absorbed by liver

  15. Transport from Adipose tissue –When energy needed • Hormones (adrenaline, glucagon, cortisol) activate hormone sensitive lipase in Adipose Tissue • Triglyceride  3 Fatty acid + Glycerol • Released from adipose to blood • Fatty acid disrupts membranes • Fatty acid bound to albumin – protects membranes • Fatty acid goes to tissues (eg muscle & liver) for energy • Glycerol goes to liver for gluconeogenesis

  16. In cell (eg liver, muscle), FA linked to coenzyme A by high energy bond Required ATP, releases AMP and PPi 2 x high energy ~phos bonds used

  17. Carnitine Shuttle CoA can not enter mitochondria Outer membrane: After activation FA-CoA transfers FA to carnitine to produce fatty acyl-carnitine- enzyme inhibited by malonyl CoA Inner membrane: FA transferred back to CoA, carnitine recycles

  18. b-Oxidation of saturated fatty acid • Dehydrogenase (oxidation) at b-carbon with FAD reduced and trans == formed • Hydratase, hydrates double bond • Dehydrogenase with NAD reduced • Thiolase cleavage with release of acetyl CoA and CoA on shortened fatty acid

  19. b-Oxidation of saturated fatty acid • Dehydrogenase (oxidation) at b-carbon with FAD reduced and trans == formed • Hydratase, hydrates double bond • Dehydrogenase with NAD reduced • Thiolase cleavage with release of acetyl CoA and CoA on shortened fatty acid • Note similarity to steps of TCA cycle

  20. b-oxidation of palmitic acid 16 carbon fatty acid 7 cycles yields 8 acetyl CoA 7 FADH2 7 NADH + H+ Which gives 131 ATP Equivalent of 2 ATP used in activation of FA:- net 129 ATP

  21. Palmitic acid yields >2x ATP per gram compared to glucose Fatty acids have no water of hydration

  22. If FA has odd number of carbons, b-oxidation proceeds till C3 fatty acyl CoA (propionyl CoA) Carboxylase requiring biotin Racemase (isomerase) converts between sterioisomers Mutase – internal transfer of carboxyl group- required Vit B12 Succinyl CoA to TCA cycle and gluconeogenesis THIS IS VERY IMPORTANT FOR RUMINANTS

  23. b-Oxidation of poly unsaturated fatty acid b-oxidation operates for saturated FA (no double bonds) When unsaturated other enzymes are involved for oxidation of double bonds Reaction requires 2 x isomerases and NADPH dependent reductase as well as the usual enzymes Altered reaction costs 5 ATP per double bond

  24. Catabolism of lipid Stimulated by hormone, (glucagon, adrenalin) Adipose tissue releases FA & glycerol In liver & muscle FA is activated & enters mitochondria Oxidised to acetyl CoA & enters TCA cycle In liver,excess acetyl CoA forms ketone bodies, secreted to blood & used in other tissues (not brain)

  25. Control of lipid catabolism • Whole animal level • Hormone sensitive lipase • Triglyceride  fatty acid + glycerol • Activated by glucagon, adrenaline • Cellular regulation • Carnitine shuttle inhibited by malonyl CoA • Malonyl CoA is a reactant in FA synthesis • Malonyl CoA elevated when cell is energy rich

  26. Formation of Ketone Bodies In Liver (only organ with enzymes): 3 x acetyl CoA form 3-OH, 3-methyl glutaryl CoA 1 acetyl CoA released Acetoacetate* formed Reduction forms b-hydroxybutyrate* Decarboxylation forms acetone* Exported to blood Ketone bodies are more soluble that fatty acid & help to make energy available for tissues in fasting & starvation * These are the ketone bodies

  27. Ketosis of acetyl Co-A

  28. Use of Ketone Bodies In tissues (not brain in most species): b-OH butyrate & acetoacetate to acetyl CoA Enters TCA cycle for ATP production Excess production of ketone bodies occurs in metabolic diseases – diabetes mellitus, bovine ketosis, ovine toxaemia

  29. Ketones in Ruminants • Carbohydrate in diet of ruminants forms ‘volatile fatty acids’ in rumen • These are acetate C2, propionate C3 and butyrate C4 fatty acids • Butyrate converted to b-OH butyrate (ie ketone body) in rumen wall before entry to blood • Much energy for ruminant tissue metabolism come from this ketone body

  30. Lipid Anabolism – FA Synthesis • When body/cell is energy rich • Liver, adipose tissue & mammary gland • In cytoplasm, separate from b-oxidation • Substrate is acetyl CoA (2 carbons) • From glycolysis or amino acid catabolism • Exported from mitochondria by citrate shuttle • Primary product – palmitoyl CoA, (16 carbons) • Then modified - elongated, desaturated, conjugated

  31. Lipid Anabolism- FA Synthesis • Co-factors: NADPH + H+, CoA • Multi-enzyme complex • Fatty Acid Synthase complex • Control point - Acetyl CoA carboxylase • Activated by citrate; inhibited by palmitoyl CoA • Hormone activation (insulin); inhibition (glucagon) • Nutrition: cabrohydrate activates; lipid inhibits

  32. FA Synthesis in Ruminants • Fatty acid synthesis primarily in adipose tissue and mammary gland • Little synthesis in liver • Substrate: • Acetyl CoA from acetate in blood • Acetate in blood is rumen product ‘volatile fatty acid’ • Activated by acetyl CoA synthase • Acetate + CoASH + ATP  Acetyl CoA + AMP + PPi

  33. CITRATE SHUTTLE (Malate Shuttle also operates) Mitochondria Acetyl CoA + Oxaloacetate ADP, Pi carboxylase Pyruvate Citrate + CoA Citrate synthase (TCA cycle) COO- , ATP NAD+ NADH+ + H+ Malate enzyme Pyruvate Malate Oxaloacetate + Acetyl CoA + ADP + Pi Citrate + CoA + ATP Malate DH Citrate lyase NADPH+ + H+ NADP+ FATTY ACID SYNTHESIS Cytoplasm

  34. Control site for FA synthesis Acetyl CoA carboxylase, activated by citrate, inhibited by palmitoyl CoA (product) Activated by insulin, inhibited by glucagon Upregulated by hi carbon/low fat diet Downregulated by hi fat/low carbon diet

  35. Fatty acid synthase complex: 7 enzymes and acyl carrier protein (ACP) in dimer formation ACP has active –SH and binds growing FA chain Cys with –SH also present Each enzyme required for FA synthesis

  36. Reactions catalysed by fatty acid synthase Transacylase: acetyl CoA to cys-SH, malonyl CoA to ACP-SH Condensation by ketoacyl synthase: acetyl replaces carboxyl grp of malonyl, becomes C4 Reductase: C3 keto group becomes hydroxyl (NADPH) Dehydratase: hydroxyl grp lost, double bond in place Reductase: double bond is hydrogenated (NADPH) Acetyl Transacylase: C4 FA transferred to cys-SH, new malonyl to ACP-SH

  37. Fatty Acid Synthesis • Continues for 6 cycles • C16 palmitoyl Co A is released by thioesterase • Released palmitoyl CoA further modified • Elongated by addition of acetyl groups • Desaturated to give unsaturated FA • Conjugated to triglyceride and phospholipid

  38. In endoplasmic reticulum C2 groups from malonyl CoA with loss of CO2 Multi-enzyme complex needed – FA elongase Very long chain FA (22-24 carbons) needed for central nervous system In Mitochnodria Elongation by reversal of b-oxidation

  39. Example: palmitoyl CoA (C16)  Palmitoleioyl CoA C16 C16, cis D9 In endoplasmic reticulum, NADH & cytochrome b5 required

  40. In endoplasmic reticulum In Liver: glycerol-3-phos from glycerol, product (TG) goes to VLDL synthesis In adipose: glycerol-3 phos from glucose via glycolysis (no glycerol kinase), therefore only when animal has high glucose * Note error in fig: Pi released from phosphatidic acid not taken up *

  41. Control of FA synthesis • In fed state with excess of energy • Increased insulin from pancreas • Activates acetyl CoA carboxylase • Activates lipoprotein lipase in adipose tissue, increasing TG breakdown in VLDL & transfer of Fatty acid to adipocyte • Decreased glucagon – (insulin antagonist) • High glucose • Enters adipose tissue, provides glycerol, essential for TG re-synthesis

  42. Synthesis of Phospholipid • In endoplasmic reticulum • A) diacyl glycerol (as in TG formation) reacts with CDP-choline giving phosphatidyl choline and CMP • Same with CDP-serine & CDP-ethanolamine • B) phosphatidic acid (TG formation), react with CTP to form CDP-diacyl glycerol then with inositol to form phosphatidyl inositol • From endoplasmic reticulum to membranes

  43. Synthesis of cholesterol Liver predominant site Acetyl CoA to mevalonate 3 x acetyl CoA forms HMG CoA (as in ketone formation) Reduction to mevalonate (C6) Converted to isopentenyl pyro phosphate (C5; diphosphate) 5 x isopent pyrophos condensed to give squalene

  44. Natural conformation of squalene encourages ring formation by cyclase

  45. Cholesterol • Forms cholesterol ester for transport in VLDL (enzyme is LCAT) • Forms bile acids with glycine, taurine for digestion • Modifications lead to hormones • No degradation in body (ie no enzyme to break ring structure)

  46. Regulation of cholesterol synthesis • Committing enzyme:- 3-hydroxy 3-methyl glutaryl reductase (formation of mevalonic acid) • Control by cholesterol concentration in cell • Hi chol inhibits: low chol activates • Control by hormones • Insulin & thyroid hormone activates: glucagon & cortisol inhibit • Control by diet • Enzyme synthesis increases in fasting • Enzyme synthesis decreases when dietary cholesterol is high • Target for ‘statin’ drugs