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- 1. 1
- 3. Outline 1. Introduction 2. Digestion and absorption in GI 3. Formation and secretion of lipoproteins (chylomicron) by enterocytes 4. Blood circulation and targeting of dietary lipids and lipoproteins 5. Destination of fatty acids in tissues 6. Lipid transport in fed state 7. Lipid transport in fasted state 8. Oxidation of fatty acids 3
- 4. 1. Importance of lipids and lipoproteins • Heterogeneous group of water insoluble organic molecules • Major source of energy (9Kc/1gr) • Storage of energy (TAG in adipose tissue) • Amphipatic barriers (PL, FC) • Regulatory or coenzyme role (vitamins) • Control of body’s homeostasis (steroid hormones, PG) • Consequences of imbalance in lipids and lipoproteins metabolism: – Atherosclerosis – Obesity – Diabetes 4
- 5. 1. Importance of lipids and lipoproteins 5 Atherosclerosis Obesity
- 6. Lipid metabolism 2. Digestion and absorption of Dietary fats in GI 6
- 7. 2.1. Dietary fats contents • Triacylglycerol (TAG) – Over 93% of the fat that is consumed in the diet is in the form of triglycerides (TG) or TAG • Cholesterol (FC, CE) • Phospholipids (PL) • Free fatty acids (FFA) 7
- 8. 2.2. Dietary sources of Lipids • Animal Sources • Vegetable Sources 8
- 10. 2.3. Digestion of dietary fats Digestion in stomach Lingual lipase -----acid stable Gastric lipase -----acid stable • These enzymes are most effective for short and medium chain fatty acids • Milk, egg yolk and fats containing short chain fatty acids are suitable substrates for its action • Play important role in lipid digestion in neonates 10
- 11. 2.4.Digestion in small intestine 11
- 12. 2.5. Bile Salts Bile salts are synthesized in the liver and stored in the gallbladder They are derivatives of cholesterol Bile salts help in the emulsification of fats Bile salts help in combination of lipase with two molecules of a small protein called as Colipase. This combination enhances the lipase activity 12
- 13. 2.6. Pancreatic enzymes in degradation of dietary lipids • Pancreatic Lipase (along with colipase) – Degradation of TAG • Cholesteryl estrase – Degradation of cholesteryl esters • Phospholipase A2 and lysophospholipase - Degradation of Phospholipids 13
- 15. 2.7. Control of lipid digestion Cholecystokinin Secretin Bicarbonate 15
- 16. 2.8. Disorders 1. Lithiasis 2. Cystic fibrosis 16
- 17. 2.8. Disorders: Lipid Malabsorption • Steatorrhea: increased lipid and fat soluble vitamin excretion in feces. – Possible causes of steatorrehea 17 • Colipase deficiency
- 18. 3. Absorption and secretion of lipids by enterocytes 18 TAG: triacylglycerol DAG: diacylglycerol MAG: monoacylglycerol FA: fatty acid CL: cholesterol BS: bile salt LPA: lysophosphatidate CE: cholestryl ester ACAT: acyl-CoA cholesterol acyl transferase CM: chylomicron MTP: microsomal TAG transfer protein AGPAT: 1-acylglycerol-3-phosphate-O-acyltransferase
- 19. 3. Secretion of lipids from enterocytes After a lipid rich meal, lymph is called chyle 19
- 20. 4. Blood circulation and targeting of dietary lipids and lipoproteins 20
- 21. 4. Blood circulation and targeting of lipids and lipoproteins 21
- 22. 4.1. ApoC-II, lipoprotein lipase (LPL) , deficiency and heparan sulfate 22 Glycerol Chylomicron remnant LPL HDL Liver (exogenous) Clearing factor
- 23. 6. Destination of fatty acids in tissues • Muscle tissue and liver: Catabolism (oxidation) – The end product of FAs catabolism (acetyl-CoA): • as fuels for energy production (TCA) • as substrates for cholesterol and ketone body synthesis • Adipose tissue: Storage (TAG) 23
- 24. 7. Lipids and lipopoteins transport in fed state 24 FAs TAGs Dietary TAG FAs energy Chylomicron (TAGendo) and VLDL (TAGexo) Acetyl-CoA FAs TAG Glucose & other fuels Blood stream Muscle Adipose tissue liver Small intestine
- 25. 25 8. Lipids and lipopoteins transport in long fasted state FAs+Glycerol TAGs FAs(+ketone bodies) energy FAs-albumin glycerol FAs Acetyl-CoA Ketone bodies Blood stream Muscle Adipose tissue liver Glucose Glycerol Ketone bodies Acetyl-CoA energy ketone bodies Brain
- 26. 26
- 27. • Pathway for catabolism of saturated fatty acids at the β carbon atom with successive removal of two carbon atoms as acetyl CoA • Site: – Cytosol (activation) – Mitochondria • Membrane transport • Matrix ( β oxidation) 27
- 28. 9.1.1. Activation and transport of fatty acids into mitochondria 28 Acyl CoA synthase
- 29. 9.1.1. Entry of short and medium chain FA into mitochondria • Carnitine and CAT system not required for fatty acids shorter than 12 carbon length. • They are activated to their CoA form inside mitochondrial matrix. 29
- 30. 9.1.1.1. Carnitine deficiencies • Primary causes: – Carnitine acyl transferase-I (CAT-I) deficiency: mainly affects liver – Carnitine acyl transferase-II (CAT-II) deficiency: mainly affects skeletal and cardiac muscles. • Secondary causes : – liver diseases: decreased endogenous synthesis 30
- 31. 9.1.1.1. Consequence of carnitine deficiencies • Excessive lipid accumulation occurs in muscle, heart, and liver • Cardiac and skeletal myopathy • Hepatomegaly • Low blood glucose in fasted state hypoglycemia coma 31
- 32. 32
- 33. • Provision of energy – Major pathway of acetyl-CoA • Cholesterol production • Ketone bodies production – Diabetes – Starvation 33
- 34. Types of fatty acyl CoA dehydrogenases • Long chain fatty acyl CoA dehydrogenase (LCAD) • Medium chain fatty acyl CoA dehydrogenase (MCAD) • Short chain fatty acyl CoA dehydrogenase (SCAD) MCAD deficiency is thought to be one of the most common inborn errors of metabolism. 34
- 35. 35 TAG FFA Glucagon Epinephrine + The first level The second level FFA Acetyl-CoA TCA NADH The third level CAT 1 FFA Malonyl-CoA - Acetyl-CoA and NADH inhibition of ᵦ oxidation enzymes Adipose tissue Muscle tissue and liver - Insulin
- 36. Peroxisomal FA oxidation • Acts on very long chain fatty acids (VLCFAs) • Zellweger syndrome – Absence of peroxisomes – Rare inherited disorder – VLCFA cannot be oxidized – Accumulation of VLCFA in brain, blood and other tissues like liver and kidney 36
- 37. Omega oxidation • It is a minor pathway • Takes place in microsomes • Involves oxidation of last carbon atom ( ω carbon) • More common with medium chain fatty acids 37
- 38. Alpha oxidation • Seen in branched chain fatty acid, phytanic acid • Occurs in endoplasmic reticulum • Refsum disease – Genetic disorder – Caused by a deficiency of alpha hydroxylase – There is accumulation of phytanic acid in the plasma and tissues. – The symptoms are mainly neurological. 38
- 39. Acetyl CoA and lipid metabolism 39 TAG - Protein -Glucose Acetyl-CoA TCA Ketone bodies HMG-CoA GLC Protein TAG & PL HMG-CoA Cholesterol Pentose phosphate pathway FA Mitochondria Cytosol
- 40. De Novo synthesis of fatty acids • Saturated fatty acids are synthesized from acetyl CoA • Occurs in cytoplasm • Occurs mainly in liver, adipose tissue and lactating mammary gland • Need to – acetyl CoA – NADPH 40
- 41. De Novo synthesis of fatty acids • Phase I – Transport of substrates into cytosol – Carboxylation of acetyl-CoA to malonyl-CoA • Phase II – Utilization of substrate to form palmitate by fatty acid synthase complex • Phase III – Elongation and desaturation of palmitate to generate different fatty acids 41
- 42. Acetyl CoA activation and regulation of it 42 Glucagon and epinephrine +
- 43. Synthesis of palmitate by fatty acid synthase(FAS) 43
- 44. Modification of dietary and endogenous fatty acids • Chain elongation to give longer fatty acids • Desaturation, giving unsaturated fatty acids 44
- 45. Modification of dietary and endogenous fatty acids 45 ω-7 ω-9 ω-6 ω-3 Essential fatty acids
- 46. 46 Glycerol Glucose Dihydroxy acetone phosphate 1acyl-dihydroxy acetone phosphate Pyruvate Glycerol 3-P 1acyl- glycerol 3-P 1,2Diacyl- glycerol 3-P (phosphatidate) Diacylglycerol TAG Monoacylglycerol Acyl-CoA CoA Acyl-CoA CoA Pi Acyl-CoA CoA Acyl-CoA CoA Acyl-CoA CoA ATP ADP NADH, H+ NAD+ NADH, H+ NAD+ TAG formation
- 47. Fates of TAG in liver and adipose tissue • Adipose tissue: TAG stored in cytosol • Liver: very little stored. Exported out of liver in VLDL , which exports endogenous lipids to peripheral tissues 47
- 48. 48 FFA Lipolysis
- 49. Mobilization of stored fats and release of FAs 49 HSL HSL-P P P P P P P Glucagon & epinephrine +
- 51. Cholesterol 51
- 52. Cholesterol importance • Membrane component • Steroid synthesis • Bile acid/salt precursor • Vitamin D precursor • It is synthesized in many tissues from acetyl-CoA and is eliminated from the body in the bile salts 52
- 53. Liver cholesterol pool Diet De novo synthesis Cholesterol synthesized in extrahepatic tissues Liver cholesterol pool Free cholesterol In bile Conversion to bile salts/acid Secretion of HDL and VLDL 53
- 54. Cholesterol Synthesis • Occurs in cytosol • Requires NADPH and ATP • All carbons from acetyl-CoA • Highly regulated • Site : Liver, adrenal cortex, testis, ovaries And intestine. • All nucleated cells can synthesize cholesterol. • Area :The enzymes of synthesis are located partly in endoplasmic reticulum and partly in cytoplasm. 54
- 56. Regulation of Cholesterol synthesis Covalent modification 56
- 57. Regulation of Cholesterol synthesis • Regulation at transcription 57
- 59. CORE CHOLESTEROL ESTERS TRIGLYCERIDES MONOLAYER OF PHOSPHOLIPID AND CHOLESTEROL INTEGRAL APOPROTEINS PERIPHERAL APOPROTEIN Structure of lipoprotein 59
- 60. Apoproteins A B C E A-I Liver& intestine A-II Liver B-48 Intestine B-100 Liver C-l C-ll C-lll All Liver Liver 60
- 61. Classification Based on density by ultracentrifugation i. Chylomicrons ii. Very Low Density Lipoprotein iii. Intermediate Density Lipoprotein iv. Low Density Lipoprotein v. High Density Lipoprotein 61
- 62. Composition and size of lipoprotein 62
- 64. Exogenous cycle(Metabolism of CM) 64
- 66. HDL- cholestrol metabolism reverse cholesterol transport and LDL metabolism 66
- 67. • Regulated: by LDL receptor • Unregulated : by scavenger receptor(SR) 67
- 68. Regulated: by LDL receptor 68
- 69. regulated LDL uptake by LDL receptor 69
- 70. Antioxidants Free radicals + - Scavenger receptor Unregulated LDL uptake by scavenger receptor 70 Atherosclerosis
- 71. • Atherosclerosis is a form of arteriosclerosis in which thickening and hardening of the vessel are caused by the accumulation of lipid-laden macrophages or foam cell within the arterial wall, which leads to the formation of a lesion called a plaque • Atherosclerosis is not a single disease • It is the leading contributor to coronary artery and cerebrovascular disease Atherosclerosis 71
- 73. Hypercholesterolemia • Normal serum cholesterol level 150-200mg/dl • Increased cholesterol level is seen in following conditions diabets mellitus, lipid nephrosis, hypothyroidism • Atherosclerosis • Xanthomas (deposition of cholesterol in subcutaneous tissue) • Corneal arcus (deposits of lipid in cornea) 73
- 74. Fredrickson classification of the hyperlipidemias 74
- 75. Degradation of Cholesterol • Synthesis of bile acids Excretion in the feces 75
- 76. 76
- 77. Cholesterol-lowering drugs • Statins • Fibric acid derivatives • Niacin • Bile-acid resins • Cholesterol absorption inhibitors 77
- 78. Ketone bodies 78
- 79. Ketone bodies • Ketone bodies are metabolic products that are produced in excess during excessive breakdown of fatty acids 79 Acetone Acetoacetate β- hydroxybutyrate
- 80. Ketone bodies importance • Alternate sources to glucose for energy • Production of ketone bodies under conditions of cellular energy deprivation • Utilization of ketone bodies by the brain 80
- 81. ketone bodies production and utilization 81 HMG-CoA synthase
- 82. • By availability of acetyl CoA • Level 1 – Lipolysis • Level 2 – Entry of fatty acid to mitochondria • Level 3 – Oxidation of acetyl CoA 82
- 83. 83
- 84. Diabetic Ketoacidosis 84 With each ketone body, one hydrogen atom is released in bloodlowering of pH Acidosis.
- 85. Metabolism of complex lipids Phospholipids • Polar, ionic compounds • alcohol • Phosphodiester bridge • Diacylglycerol or Sphingosine • Types: – Glycerophospholipids – Sphingophospholipids (sphingosine) 85
- 86. Synthesis of phospholipids • Synthesized in smooth endoplasmic reticulum. • Transferred to Golgi apparatus • Move to membranes of organelles or to the plasma membrane or released out via exocytosis • All cells except mature erythrocytes can synthesize phospholipids 86
- 87. Synthesis of Glycerophospholipids • Biosynthesis of anionic Glycerophospholipids – Phosphatidylglycerol(PG) – Phosphatidylinositol(PI) – Cardiolipin • Biosynthesis of neutral glycerophospholipids – Phosphatidylcholine(PC) – Phosphatidylethanolamine(PE) • 87
- 88. Synthesis of Glycerophospholipids • First strategy: • biosynthesis of anionic Glycerophospholipids – CTP:phosphatidate citidyl transferase: 88 Alcohol CMP R1 R2 OP R1 R2 CDP R1 R2 phosphoalcohol CTP PPi Phosphatidate CDP-DAG Phosphatidyl alcohol
- 89. Synthesis of Glycerophospholipids • Second strategy: • Biosynthesis of neutral glycerophospholipids – CTP:phospho alcohol citidyl transferase: 89 R1 R2 OH R1 R2 phosphoalcohol DAG Phosphatidyl alcohol Alcohol Phosphoalcohol CDP-alcohol CMP
- 91. Sphingomyelin synthesis • Ceramide is required for sphingomyelin synthesis 91 PC DAG
- 92. Degradation of glycerophospholipids • Phospholipases remove one fatty acid from C1 or C2 and form lysophosphoglyceride. • Lysophospholipases act upon lysophosphoglycerides. – Phospholipase A1 – Phospholipase A2 – Phospholipase C – Phospholipase D 92
- 93. Phospholipases Phospholipse Product Significant A1 FA--- 1-lysophospholipid Phospholipid transformation A2 FA--- 2-lysophospholipid Phospholipid transformation, Eicosanoid synthesis B FA---- Glycerol 3-phosphoalcohol Lysophospholipid degradation C Phosphoalcohol---1,2DAG Secondary messenger production D Alcohol---- phosphatidic acid Secondary messenger production 93
- 94. Degradation of Sphingomyelin • Sphingomyelinase • Ceramidase • Sphingosine and ceramide act as intracellular messengers. 94
- 95. Glycolipids • Carbohydrate and lipid components • Derivatives of ceramide • Essential components of all membranes, greatest amount in nerve tissue • Interact with the extracellular environment • No phospholipid but oligo or mono-saccharide attached to ceramide by O-glycosidic bond. 95
- 96. Classes of Glycosphingolipids • Neutral glycosphingolipids : – Cerebrosides – Globosides • Acidic glycosphingolipids: – Ganglioside – Sulfatides 96
- 97. Synthesis of Neutral Glycosphingolipids • Site: – Golgi apparatus • Subtrates – Ceramide, sugar activated by UDP • Galactocerobrosides – Ceramide + UDP- galactose • Glucocerebrosides – Ceramide + UDP – glucose • Enzymes – Glycosyl transferases 97
- 98. Synthesis of Acidic Glycosphingolipids • Gangliosides – ceramide + two or more UDP- sugars react together to form Globoside. – NANA combines with globoside to form Ganglioside. 98
- 99. Synthesis of Acidic Glycosphingolipids • Sulfatides – galactocerebroside gets a sulphate group from a sulphate carrier with the help of sulfotransferase and forms a sulfatide. 99
- 100. Degradation of glycosphingolipids • Done by lysosomal enzymes • Different enzymes act on specific bonds hydrolytically ---- the groups added last are acted first. 100
- 101. Sphingolipidoses • Lipid storage diseases • Accumulation of sphingolipids in lysosomes • Partial or total absence of a specific hydrolase • Autosomal recessive disorders 101
- 103. Eicosanoids are classified in to two main groups- 1) Prostanoids 2) Leukotrienes and Lipoxins Prostanoids are further sub classified in to three groups- a) Prostaglandins(PGs) b) Prostacyclins(PGIs) c) Thromboxanes (TXs) Eicosanoids- Classification 103
- 104. Characteristic features of prostaglandins 1) Act as local hormones 2) Show the autocrine and Paracrine effects 3) Are not stored in the body 4) Have a very short life span and are destroyed within seconds or few minutes 5) Production increases or decreases in response to diverse stimuli or drugs 6) Are very potent in action. Even in minute (ng concentration), biological effects are observed. 104
- 105. Synthesis of eicosanoids • Linoleic acid is the dietary precursor of PGs. • Arachidonic acid is formed by elongation and desaturation of linoleic acid. • Membrane bound phospholipids contain arachidonic acid. • Phospholipase A2 causes the release of arachidonic acid from membrane phospholipids. 105
- 106. Synthesis of eicosanoids 106 Steroidic anti- inflammation drugs NSAIDs