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Chapter 5. Metabolism of Lipids

Chapter 5. Metabolism of Lipids. Lipids Insoluble or immiscible Triacylgerols store and supply energy for metabolism . Lipoids: phospholids, glycolipids, cholesterol and cholesterol ester membrane components. Metabolism of lipid. Fatty acids esterified to some backbone molecules

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Chapter 5. Metabolism of Lipids

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  1. Chapter 5.Metabolism of Lipids Lipids Insoluble or immiscible Triacylgerols store and supply energy for metabolism. Lipoids: phospholids, glycolipids, cholesterol and cholesterol ester membrane components

  2. Metabolism of lipid • Fatty acids esterified to some backbone molecules glycerol sphingosine cholesterol

  3. Metabolism of Lipids Fats store in adipose tissue Essential fatty acids: formation of membrane, regulation of chollesterol metabolism, precursors of eicosanoids (protaglandins, thromboxanes and leukotrienes. Necessary unsaturated fatty acids

  4. Fat Facts • Dietary lipids are 90% triacylglycerols; also include cholesterol esters, phospholipids, essential unsaturated fatty acids; fat soluble vitamins (A,D,E,K) • Fat is energy rich and provides 9 kcal/gm • Normally essentially all (98%) of the fat consumed is absorbed, and most is transported to adipose for storage.

  5. SIX STEPS OF LIPID DIGESTION AND ABSORPTION • Minor digestion of triacylglycerols in mouth and stomach by lingual (acid- stable) lipase • Major digestion of all lipids in the lumen of the duodenum/jejunum by pancreatic lipolytic enzymes • Bile acid facilitated formation of mixed micelles that present the lipolytic products to the mucosal surface, followed later by enterohepatic bile acid recycling • Passive absorption of the lipolytic products from the mixed micelle into the intestinal epithelial cell • Reesterificationof 2-monoacylglycerol, lysolecithin, and cholesterol with free fatty acids inside the intestinal enterocyte • Assembly and exportfrom intestinal cells to the lymphatics of chylomicrons coated with Apo B48 and containing triacylglycerols, cholesterol esters and phospholipids

  6. Summary of the physiologically important lipases

  7. Absorption of Lipids

  8. Metabolism of Triacylglyerols

  9. LIPOLYSIS • Mobilization of fats from triacylglycerols • Hormone sensitive lipase • Rate-determining step • Specific for removing first fatty acid • Phosphorylated form is active

  10. Fatty acid + Triacylglycerol Diacylglycerol ATP HSL-a OP ADP Insulin + protein cyclic AMP phosphatase + ATP HSL-b Pi OH (inactive form) AMP caffeine theophylline - cell membrane HORMONES Epinephrine Glucagon Adenylyl cyclase active protein kinase A RECEPTORS inactive phosphodiesterase + = activation - = inhibition HSL = hormone-sensitive lipase Figure 1. Hormonal activation of triacylglycerol (hormone-sensitive) lipase. Phosphorylation brings about activation to HSL-a.

  11. lipolysis Glycerols and fatty acids diffuse out of adipose cells and enter into circulation Free fatty acids (FFA) form fatty acid-albumin complexes Glycerols to form dihydroxyacetone phosphate (DHAP) Figure. Page 176

  12. Beta-Oxidation of Fatty Acids

  13. Beta Oxidation Part I The break down of a fatty acid to acetyl-CoA units…the ‘glycolysis’ of fatty acids STRICTLY AEROBIC Occurs in the mitochondria Acetyl-CoA is fed directly into the Krebs cycle Overproduction causes KETOSIS Exemplifies Aerobic Metabolism at its most powerful phase

  14. ATP PPi HS-CoA AMP CH3CH2CH2COOH [CH3CH2CH2CO-AMP] Acyl-CoA synthetase CH3CH2CH2CO~SCoA Fatty acyl CoA Prepares a Fatty Acid for transport and metabolism

  15. Knoop’s Experiment Phenylacetate Benzoate

  16. Beta-Oxidation of Fatty Acids

  17. THE ENERGY STORY Glucose C6H12O6 + 6O2  6CO2 + 6H2O Ho = -2,813 kJ/mol = - 672 Cal/mol = 3.74 Cal/gram Stearic Acid C18H36O2 + 26O2 18CO2 + 18 H2O Ho = -11,441 kJ/mol = - 2,737 Cal/mol = 9.64 Cal/gram On a per mole basis a typical fatty acid is 4 times more energy rich that a typical hexose

  18. Sample calculation of energy produced for the cell via b-oxidation of palmitate (a C16 fatty acid):

  19. Palmitoyl-CoA Palmitoyl-CoA + 7CoA + 7FAD + 7NAD+ + 7H2O 8 Acetyl-CoA 80 ATP 7 FADH2 10.5 ATP 7 NADH + 7H+ 17.5 ATP 108 ATP -2 ATP Total 106 ATP

  20. Beta Oxidation Part II 3 Obstacles Unsaturated fatty acid Obstacle of cis double bonds Polyunsaturated fatty acid Obstacle of position of double bond Odd number chain fatty acid Obstacle of 3 carbons at the end

  21. H H C=C CH3CH2CH2CH2CH2C CH2CH2CH2CH2CH2CH2CH2CO~SCoA Whoops! 4 2 3 4 1 1 2 3 5 H H H H C=C C=C CH3CH2CH2CH2 CH2 CH2CH2CH2CH2CH2CH2CH2CO~SCoA Oleic Acid C18:cis9 A cis D.B. will interfere Linoleic

  22. New  carbon Cleavage here 9 H H C=C CH3CH2CH2 CH2CH2CH2-CO~SCoA New COO group 9 H 8 7 CH2C CH3CH2CH2 C-CO~SCoA H Unsaturated and Polyunsaturated Require Additional Enzymes 8 7 Enoyl CoA Isomerase Trans double bond

  23. H H H H 9 C=C C=C CH2-CH2 CH2 CH2-CH2-CH2-CH2-CH2-CH2CH2C~SCoA O CH3C~SCoA CH3C~SCoA CH3C~SCoA CH2C~SCoA CH2C~SCoA CH2C~SCoA O O O O O O 6 5 4 3 2 1 4 1 3 2 Linoleic Acid C18 cis9,12

  24. 9 -CH2 CH2 CH2CO~SCoA -CH2 CH2 -CH2 CH2 C-CO~SCoA H H H H H H H H H H C=C C=C CH2CO~SCoA C=C C=C C-C H Round 4 starter Round 5 starter Beta carbon to be Poly Unsaturated (Continued) Enoyl-CoA isomerase

  25. beta 6 -CH2 CH2 H FAD H H H H H H C=C C=C C-CO~SCoA C=C CH2CO~SCoA H FADH2 C Round 5 starter CO~SCoA CH2 Dead end Acyl-CoA dehydrogenase New Strategy

  26. H beta 6 H CH2 C CH2CO~SCoA NADPH + H+ C H H NADP+ H C=C C-CO~SCoA H beta 6 beta 6 H -CH2 CH2 C-CO~SCoA C C H Reduce near (bond), Shift far (bond) 2,4 dienoyl-CoA reductase 3,2 enoyl-CoA isomerase Continue Beta Oxidation

  27. Ketone bodies formation and utilization

  28. CH3CCH2COO-  H CH3CCH2COO- O O OH CH3-C-CH3 What is Ketosis? An excessive production of ketones in the blood 3 derivatives of acetyl-CoA Acetoacetate -hydroxybutyrate Acetone

  29. What is the Significance of ketosis Acidosis Excessive acid in the blood Overflow Excessive oxidation of fatty acids Metabolic Problem Faulty Carbohydrate Metabolism

  30. Metabolic fate of Acetyl CoA Pyruvate minor Acetyl-CoA Fatty Acids Ketone Bodies major Citrate

  31. CH3C~SCoA CH3C~SCoA CH2C~SCoA O O O O O CH3CCH2C~SCoA HS-CoA CH3C + -Ketothiolase rearrangement OH Acetoacetyl-CoA

  32. HS-CoA CH3CCH2C~SCoA HO OH O O O O O O OOC-CH2-C-CH2-C~SCoA CH3CCH2C~SCoA CH2C-O- CH3C~SCoA CH3 HMG-CoA Synthase -hydroxy--methyl glutaryl-CoA (HMG-CoA)

  33. CH3-C~SCoA OH OOC-CH2-C-CH2-C~SCoA Acetoacetate CH3 OH O O O O O OOC-CH2-C-CH3 NADH + H+ OOC-CH2-C-CH2-C~SCoA CO2 NAD+ CH3 CH3-C-CH3 OOC-CH2-CH-CH3 OH HMG-CoA HMG-CoA Lyase + Acetone -hydroxybutyrate

  34. Utilization of ketone bodies Acetoacetate/succinyl-CoA CoA transferase Acetoacetyl-CoA thiokinase Acetoacetyl-CoA thiolase Page 180

  35. Pysiological Significance of ketogenesis Ketone bodies produced by the liver are excellent fuels for a variety of extrahepatic tissues, especially during times of prolonged starvation. Reconversion of ketone bodies to acetyl-CoA inside the mitochondria provides metabolic energy.

  36. Regulation of Ketogenesis Feeding status In the hungry state, higher glucagon and other lipolytic hormones trigger the lipolytic process in adipose tissue with the result that free fatty acids pass into the plasma for uptake by liver and other tissues. This promotes fatty acid oxidation and ketogenesis in the liver.

  37. Regulation of Ketogenesis Metabolism of glycogen in the hepatic cells once fats enter the liver, they have two distinct fates: activated to acyl-Co-A and oxidized, or esterified to glycerol in the production of triacylglycerols in cytoplasm. If the liver has sufficient supplies of glycerol-3 phosphate by glucose metabolism, most of the fats will be turned to the production of triacylglycerols. In contrast, glucose deficiency will cause a lower triacylglycerols and ATP generation, with the majority of the FAs entering beta-oxidation leading to a increased production of ketone bodies.

  38. Regulation of Ketogenesis The fall in malonyl-CoA concentration can terminate the inhibition on carnitine acyltransferase I, such that long-chain fatty acids can be transported through the inner mitochondrial membrane to the enzymes of fatty acid oxidation and ketogenesis. This may happen during a hungry state. In contrast, administration of food after a fast, or of insulin to the diabetic subject, reduces plasma free fatty acid concentrations and increases liver concentration of malonyl-CoA, this will inhibit carnitine acyltransferase I and thus reverses the ketogenic process.

  39. Fatty Acid Biosynthesis Not exactly the reverse of degradation by a different set of enzymes , in a different part of the cell Primarily in the cytoplasm of the following tissues: liver, kidney, adipose, central nervous system and lactating mammary gland Liver is the major organ for fatty acid synthesis

  40. LIPID BIOSYNTHESIS • Fatty acid biosynthesis-basic fundamentals • Fatty acid biosynthesis-elongation and desaturation • Triacylglycerols • Phospholipids • Cholesterol • Cholesterol metabolism

  41. Cytosol Requires NADPH Acyl carrier protein D-isomer CO2 activation Keto  saturated Mitochondria NADH, FADH2 CoA L-isomer No CO2 Saturated  keto Fatty Acid Biosynthesis Synthesis Beta Oxidation

  42. Rule: Fatty acid biosynthesis is a stepwise assembly of acetyl-CoA units (mostly as malonyl-CoA) ending with palmitate (C16 saturated) 3 Phases Activation Elongation Termination

  43. Cofactor CH3C~SCoA O O ATP HCO3- ADP + Pi CO2 -OOC-CH2C~SCoA active carbon Biocytin ACTIVATION Biotin Acetyl-CoA carboxylase Carboxybiocytin

  44. Acetyl-CoA CarboxylaseThe rate-controlling enzyme of FA synthesis • In Bacteria -3 proteins (1) Carrier protein with Biotin (2) Biotin carboxylase (3) Transcarboxylase • In Eukaryotes - 1 protein (1) Single protein, 2 identical polypeptide chains • (2) Each chain Mwt = 230,000 (230 kDa) (3) Dimer inactive (4) Activated by citrate which forms filamentous form of protein that can be seen in the electron microscope

  45. Yeast Fatty Acid Synthase Complex 2,500 kDa Multienzyme Complex 6 molecules of 2 peptide chains called A and B (66) A: (185,000) Acyl Carrier protein -ketoacyl-ACP synthase (condensing enzyme) -ketoacyl-ACP reductase B: (175,000) -hydroxy-ACP dehydrase enoyl-ACP reductase palmitoyl thioesterase Fatty Acid Synthase Complex

  46. H CH3 H HO O ACP HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-CH2-Ser- O O O H H H CH3 H HO O O HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-P-O-CH2 Adenine O O O O O H H H O OH O-P-O OH Acyl Carrier Protein Phosphopantetheine Cysteamine Acyl carrier protein 10 kDa Coenzyme A

  47. Initiation CH3C~SCoA CH3C- ACP ACP + HS-CoA O O O O -OOC-CH2C~S- CH2C~S- Overall Reaction Malonyl-CoA + ACP Acyl Carrier Protein CO2 HS-CoA NOTE: Malonyl-CoA carbons become new COOH end Nascent chain remains tethered to ACP CO2, HS-CoA are released at each condensation

  48. -Carbon CH3C- ACP ACP ACP O O O O O H D isomer CH3C- HO H CH2C~S- = C- C~S- CH2C~S- CH3C- H CH3CH2CH2C~S- ACP Elongation Reduction NADPH -Ketoacyl-ACP reductase Dehydration -H2O  -Hydroxyacyl-ACP dehydrase NADPH Reduction Enoyl-ACP reductase

  49. O Free to bind Malonyl-CoA -CH2CH2CH2C~S- ACP TERMINATION Ketoacyl ACP Synthase -KS Transfer to Malonyl-CoA Transfer to KS -S-ACP Split out CO2 CO2 When C16 stage is reached, instead of transferring to KS, the transfer is to H2O and the fatty acid is released

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