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Metabolism of Lipids - I

Metabolism of Lipids - I. HP Kedilaya. Biological importance. Lipids are unique hydrophobic nature. partly obtained from foods and partly derived from carbohydrates. Fats are stored in adipocytes as highly concentrated sources of energy and oxidized for energy production.

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Metabolism of Lipids - I

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  1. Metabolism of Lipids - I HP Kedilaya

  2. Biological importance • Lipids are unique hydrophobic nature. • partly obtained from foods and partly derived from carbohydrates. • Fats are stored in adipocytes as highly concentrated sources of energy and oxidized for energy production.

  3. Biological importance • The layer of fat as adipose tissue under the skin acts as shock absorbing cushions and also thermoinsulationagainst heat loss

  4. Biological importance • Glycerophospholipids, sphingolipids and cholesterol are indispensible for cell structure and function. • Vitamin D, bile salts and steroid hormones are synthesized from cholesterol. • Prostaglandins, leukotrienes, thromboxanes and related compounds, synthesized from C20 fatty acids possess many biological actions.

  5. Contents: •  Metabolism of fatty acids Fatty acid oxidation and Fatty acid synthesis • Metabolism of Ketone bodies Ketogenesis and Ketolysis • Metabolism of Triacylglycerol • Metabolism of Compound lipids • Metabolism of Cholesterol • Metabolism of lipoproteins • Fatty liver & lipotropic factors

  6. Overview of Fatty Acid and Fat Metabolism VLDL (transported in blood, TAG delivered to (exported from Liver) adiposites for storage) TAG(Fat) Esterification Lipolysis (Liver) (Adipocytes ) Fatty acids TAG (Diet) Fatty acid synth (Lipogenesis) β-Oxidation (Liver, Adipocytes) (in all cells for energy) Carbohydrates, Amino acids (Diet) Acetyl CoA Ketone bodies Ketogenesis (Liver ) (for energy, especially in brain during starvation ) TCA cycle in all cells for energy

  7. Metabolism of Fatty Acids- includes – • Fatty Acid Oxidation (breakdown for energy) • Fatty Acid Synthesis (Lipogenesis) – De Novo synthesis of fatty acids. (‘De Novo synthesis’ refers to synthesis of complex/large molecules from simple, small molecules.) and • Ketone body metabolism

  8. Fatty acid oxidation • Fatty acids are oxidized in the body for energy mostly by β-oxidation. • Other forms of oxidation, of minor importance, are • α-oxidation and • ω-oxidation.

  9. β-Oxidation of Fatty Acids • Definition β-oxidation of fatty acids is the oxidation on the β-carbonatom of the fatty acid molecule and it occurs for the energy requirement of the cell during the fastingstate. • Tissues: Most of the tissues except brain, RBC and adrenal medulla • Starting substrate: Fatty acid(Palmitic acid as example) • Pathway/Reactions of β-Oxidation

  10. Pathway/Reactions of β-Oxidation β-Oxidation consists of the following three stages1. • Activation of fatty acids (in cytosol) II. Transport of fatty acids into mitochondria III. β-Oxidation proper (in the mitochondrial matrix)

  11. Fatty Acid Activation (in Cytosol) Fatty acid (Palmitic acid) CoASH ATP Mg2+ Thiokinase (Acyl CoA synthetase) AMP + 2Pi Acyl CoA (Palmitoyl CoA)

  12. Transport of Fatty Acyl CoA Into Mitochondria (Role of Carnitine in Oxidation of Fatty Acids) • Long chain fatty acids cannot pass through the inner mitochondrial membrane. Hence, this needs a transport mechanism involving, • carnitine, Carnitine is β-hydroxy γ-trimethyl ammonium butyrate. (CH3)3N+–CH2–CH(OH)–CH2–COO– and three proteinmolecules present in the mitochondrial membranes – • translocase, • carnitineacyltransferase (CAT I) and • carnitineacyltransferase (CAT II).

  13. Figure: Transport of fatty acyl CoA from cytosol to mitochondrial matrix CoASH Acyl CoA CAT I Acyl carnitine Carnitine CYTOSOL Translocase Inner Mitochondrial Membrane MITOCHONDRIAL MATRIX CAT II Acyl carnitine Carnitine Acyl CoA CoASH β-Oxidation

  14. III . β-Oxidation Proper(Palmitic acid/PalmitoylCoA as example) Subcellular site: Mitochondrial matrix Starting substrate:AcylCoA/PalmitoylCoA During β-oxidation, fatty acids undergo oxidative removal of successive two-carbon units as acetyl CoA, starting from carboxyl end of fatty acyl chain.

  15. III. β-Oxidation Proper Fatty Acyl CoA Mitochondrial matrix β-Oxidation ETC Acetyl CoA NADH, FADH2 ATP TCA Cycle

  16. III . β-Oxidation Proper Each cycle of β-oxidation, accompanied by removal of a two-carbon unit as acetyl CoA, has four steps/reactions in the following order. • Dehydrogenation • Hydration • Dehydrogenation • Thiolytic cleavage

  17. III . β-Oxidation Proper • Palmitic acid (C16) requires 7 cycles of β-oxidation, each cycle producing one molecule each of acetyl CoA, NADH and FADH2.

  18. Reactions of β-Oxidation of Acyl CoA (Palmitoyl CoA as Example) Acyl CoA (Palmitoyl CoA) FAD Acyl CoA dehydrogenase ETC 1.5 ATP FADH2 Δ2 – Transenoyl CoA H2O NADH Enoyl CoA hydratase FADH2 β-Hydroxyacyl CoA NAD+ β-Hydroxyacyl CoA dehydrogenase ETC 2.5 ATP NADH + H+ β-Ketoacyl CoA ATP CoASH Thiolase 6 more cycles ETC Acyl CoA + Acetyl CoA (2 carbon less) TCA cycle

  19. III . β-Oxidation Proper • Overall reaction of β-oxidation of palmitoyl CoA • Palmitoyl CoA+7 CoASH+ 7 FAD+7NAD++7 H2O • 8 Acetyl CoA+ 7FADH2 +7NADH + 7H+

  20. Energetics of β-Oxidation of Palmitic acid • MechanismATP Yield • I. β-Oxidation proper (7 cycles): • 7 NADH (by oxidative phosphorylation, • each NADH gives 2.5 ATP) 17.5 • 7 FADH2(by oxidative phosphorylation, • each FADH2 gives 1.5 ATP) 10.5 • II. From 8 acetyl CoA oxidized by TCA Cycle, • Each acetyl CoA provides 10 ATP 80 •  Total energy from one mole of palmitoyl CoA 108 • Energy utilized for activation (formation of palmitoyl CoA) –2 Net ATP yield of β-oxidation of one molecule of palmitate = 106

  21. Regulation of β-Oxidation • by availability of the substrate, namely fatty acids. • During fasting state rate of β-oxidation is increased due to high level of plasma free fatty acid, which is released from adipose tissue because of low insulin/glucagon ratio found during fasting. (See chapter ‘Lipolysis in Adipose Tissue’)

  22. Regulation of β Oxidation • by availability of the substrate, namely fatty acids. • During fed state rate of β-oxidation is decreased as there is an increased level of malonylCoA, a substrate of fatty acid synthesis. CAT I is inhibited by malonylCoA decreasing the entry of fatty acids into mitochondrial matrix.

  23. Regulation of β Oxidation fasting state ↓insulin/glucagon ratio ↑Lipolysis adipose tissue ↑plasma free fatty acid ↑β-Oxidation

  24. Oxidation of Odd Chain Fatty acids Odd chain fatty acid Several rounds of β-oxidation Propionyl CoA Succinyl CoA Acetyl CoA (Intermediate of TCA cycle)

  25. Fatty Acid Biosynthesis(De Novo Synthesis of Fatty Acid) • Synthesis is not the reversal of β-oxidation. • dietary carbohydrates and amino acids, when consumed in excess, converted to fatty acids and stored as triacylglycerols.

  26. Fatty Acid Biosynthesis(De Novo Synthesis of Fatty Acid) • Tissues: Liver, adipose tissue, kidney, brain and mammary glands • Intracellular site: Cytosol • Substrates required: Acetyl CoA, ATP and NADPH (provides reducing equivalents; main source: HMP shunt pathway)

  27. Fatty Acid Biosynthesis(De Novo Synthesis of Fatty Acid) Steps of fatty acid synthesis include: • Transport of acetyl CoA from mitochondrial matrix to cytosol • Formation of malonylCoA from acetyl CoA • Synthesis of fatty acid involving fatty acid synthase complex

  28. Steps 1. Transport of Acetyl CoA to Mitochondrial Matrix Acetyl CoA (C2) Oxaloacetate TCA cycle Citrate MITOCHONDRIA ATP ADP + Pi CYTOSOL Acetyl CoA (C2) Citrate ATP citrate lyase Oxaloacetate

  29. Steps 2 -- Formation of Malonyl CoA Acetyl CoA (C2) 1. Transport of acetyl CoA MITOCHONDRIA CYTOSOL Acetyl CoA (C2) CO2 ATP Acetyl CoA carboxylase Biotin 2. Formation of Malonyl CoA ADP + Pi Malonyl CoA (C3)

  30. Step 3 – Synthesis of Fatty Acid Involving Fatty Acid Synthase Complex Fatty Acid Synthase (FAS) Complex1 • FAS complex is a multienzyme complex and enzymes form a dimer with identical subunits. • The multienzyme complex facilitates easy interaction of substrates with the active sites of the enzymes.

  31. Figure: Fatty Acid Synthase Complex – A Diagrammatic Representation Functional subdivisiona Functional division Reducing Unit Acetyl transferase Ketoacyl reductase Dehydratase Substrate Entry and Condensing Unit Releasing Unit Malonyl transferase Enoyl reductase Thioesterase Ketoacyl synthase Acyl carrier protein 4´-phosphopantethein Cys Subunit SH SH division SH SH 4´-phosphopantethein Cys Ketoacyl synthase Acyl carrier protein Thioesterase Malonyl transferase Enoyl reductase Acetyl transferase Dehydratase Ketoacyl reductase

  32. Reactions of Fatty Acid Synthase Complex SH -Pan- Enz 1-Cys-SH Enzyme (FAS) SH -Cys-Enz 2-Pan-SH Malonyl CoA Acetyl/acyl CoA Malonyl transferase Acyl transferase CoASH CoASH • Enz 1-Cys-S-acyl • Enz 2-Pan-S-malonyl Acyl-malonyl-enzyme Ketoacyl synthase CO2 - Enz 1-Cys-SH - Enz 2 -Pan-S-ketoacyl Ketoacyl enzyme

  33. Enzyme (FAS) Malonyl CoA Acetyl/acyl CoA Malonyl transferase Acyl transferase CoASH CoASH • Enz 1-Cys-S-acyl • Enz 2-Pan-S-malonyl Acyl-malonyl-enzyme Ketoacyl synthase CO2 - Enz 1-Cys-SH - Enz 2 -Pan-S-ketoacyl Ketoacyl enzyme

  34. CoASH CoASH • Enz 1-Cys-S-acyl • Enz 2-Pan-S-malonyl Acyl-malonyl-enzyme Ketoacyl synthase CO2 - Enz 1-Cys-SH - Enz 2 -Pan-S-ketoacyl Ketoacyl enzyme

  35. Acyl-malonyl-enzyme Ketoacyl synthase CO2 - Enz 1-Cys-SH - Enz 2 -Pan-S-ketoacyl Ketoacyl enzyme

  36. - Enz 1-Cys-SH - Enz 2 -Pan-S-ketoacyl Ketoacyl enzyme NADPH + H+ Ketoacyl reductase NADP+ - Enz 1-Cys-SH - Enz 2 -Pan-S-hydroxyacyl Hydroxyacyl-enzyme Dehydratase H2O - Enz 1-Cys-SH - Enz 2 -Pan-S-enoyl Enoyl-enzyme

  37. Ketoacyl reductase NADP+ - Enz 1-Cys-SH - Enz 2 -Pan-S-hydroxyacyl Hydroxyacyl-enzyme Dehydratase H2O - Enz 1-Cys-SH - Enz 2 -Pan-S-enoyl Enoyl-enzyme

  38. Hydroxyacyl-enzyme Dehydratase H2O - Enz 1-Cys-SH - Enz 2 -Pan-S-enoyl Enoyl-enzyme

  39. - Enz 1-Cys-SH - Enz 2 -Pan-S-enoyl Enoyl-enzyme NADPH + H+ Enoyl reductase NADP+ - Enz 1-Cys-SH - Enz 2 -Pan-S-acyl Acyl-enzyme

  40. Enzyme (FAS) Malonyl CoA Acyl group transferred from • Enz 1-Cys-S-acyl • Enz 2-Pan-S- Enz 2 to Enz 1 malonyl - Enz 1-Cys-SH - Enz 2 -Pan-S-acyl After 7 cycles Thioesterase Acyl-enzyme Palmitate

  41. Regulation of Fatty Acid Synthesis Fed State ↑Insulin/glucagon ratio Activation Inhibiton, Malonyl CoA, Fatty acyl CoA Acetyl CoA Carboxylase (End products, High fat diet) Activation ↑Glucose (Intracellular ) ↑Citrate (Intracellular )

  42. Ketone Body Metabolism and Ketosis ketone bodies – A collective name for • Acetone, • Acetoacetate (acetoacetic acid) and • β-hydroxybutyrate (β-hydroxy butyric acid) • synthesized in the liver from fatty acids metabolic fuel molecules during prolonged fasting and Starvationespecially for brain

  43. Ketone Body Metabolism and Ketosis O CH3 – C – CH3 Acetone O O C – CH2 – C – CH3 Acetoacetate -O O OH β-hydroxy butyrate C – CH2 – CH – CH3 -O

  44. Ketone Body Metabolism and Ketosis • Ketosis, accumulation of ketone bodies in the body, a metabolic disorder seen in starvation and uncontrolled diabetes mellitus (Type 1)

  45. Ketone Body Metabolism and Ketosis Ketone body metabolism includes – • 1) Ketogenesis (synthesis of ketone bodies), • 2)Ketolysis (breakdown of ketone bodies for energy) and

  46. 1) Ketogenesis(Synthesis of Ketone Bodies) • Acetyl CoA immediate precursor However, since acetyl CoA is formed from fatty acids by β-oxidation, fatty acids are the ultimateprecursors • Site:Liver • Sub-cellularsite: Mitochondria

  47. Pathway/Reactions (Liver) Fatty acid β-oxidation Acetyl CoA + Acetyl CoA Thiolase CoASH Acetoacetyl CoA Acetyl CoA HMG CoA Synthase CoASH HMG CoA (β-Hydroxy β-Methyl Glutaryl CoA)

  48. Pathway/Reactions (Liver) Fatty acid Acetyl CoA β-oxidation HMG CoA Synthase Acetyl CoA + Acetyl CoA Thiolase CoASH Acetoacetyl CoA Acetyl CoA HMG CoA Synthase CoASH HMG CoA (β-Hydroxy β-Methyl Glutaryl CoA)

  49. Pathway/Reactions (Liver) Fatty acid Acetyl CoA β-oxidation HMG CoA Synthase Acetyl CoA + Acetyl CoA Thiolase CoASH Acetoacetyl CoA Acetyl CoA HMG CoA Synthase CoASH HMG CoA (β-Hydroxy β-Methyl Glutaryl CoA) HMG CoA Lyase Acetyl CoA Acetoacetate NADH + H+ Spontaneous CO2 β-hydroxy butyrate dehydrogenase Acetone NAD+ Exhaled by lungs (acetone is volatile) β-hydroxy butyrate

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