Cholesterol metabolism

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Cholesterol metabolism

  1. 1. CHOLESTEROL PRESENTED BY:-SILENT KILLERS
  2. 2. Flow of Presentation What is Lipids – Rajesh Conversion of VLDL to LDL – Kuldip Fatty acid oxidation – Zalak Oxidation of odd carbon - Pravin Ketone Bodies – Sachin Metabolism of Cholesterol & functions – Kishore Cholesterol Biosynthesis – Gulab Regulation of Cholesterol – Aadesh Degradation of Cholesterol - Dr.Brijesh Transport of Cholesterol – Sonu Hypercholesterolemia - Dipal
  3. 3. LIPID • Indispensable for cell structure & function. • Hydrophobic & non polar nature.
  4. 4. TRIACYLGLYCEROL • Lipid: 15-20 % of body weight in human • Triacylglycerol: 85-90 % • Stored in Adipose Tissue & serve as energy reserve of the body • Act as an insulating material in animal.
  5. 5. Why should fat be the fuel reserve of the body? • Two reason • TG are highly concentrated form of energy, yielding 9 cal/g, in contrast to Carbo. & protein- 4 cal/g. • TG are non polar & hydrophobic in nature, hence stored in pure form without any association with water. On other hand glycogen & protein are polar. One gram of glycogen combines with 2 g of water for storage.
  6. 6. Other Imp Body Lipid • Phospholipids • Glycolipids • Cholesterol • Arachidonic Acid (unsaturated fatty acid)
  7. 7. TRANSPORT OF LIPID • Insoluble lipid are solubilized in association with protein to form lipoproteins in which lipid are transported in blood stream. • Free lipids are undetectable in blood • Chylomicrons, VLDL,LDL,HDL & albumin-free fatty acid are diff lipoprotein complex.
  8. 8. CONVERSION OF VLDL TO LDL • VLDL IDL (intermediate density lipoproteins) By losing Apo-E LDL (Low Density lipoproteins) Apo- E returns to HDL
  9. 9. • Transfer of cholesterol is facilitate by Cholesterol ester transfer protein (CETP) • CETP transfers cholesterol ester from HDL to VLDL or LDL in exchange of TG (triaclyglycerol)
  10. 10. LDL • Supply cholesterol to extrahepatic tissue • It binds to specific receptor pits called known as glycoprotein on cell membrane • The shape of receptor pits is stabilized by protein called clathrin. • Apo B100 is responsible for the recognition of LDL receptors site.
  11. 11. DEFICIENCY OF LDL RECEPTORS • Elevation of plasma LDL, • Increase in plasma Cholesterol • Caused type IIa hyperbetalipoproteinemia • High risk of atherosclerosis
  12. 12. METABOILISM OF HDL • HDL are synthesized in liver as discoidal particles • Contains free cholesterol and phospholipids and apoproteins • The plasma enzyme lecithin-cholesterol acyl- transferase (LCAT) catalyses the esterification of free cholesterol present in the extra hepatic tissues and transfer it to the HDL • Apo-A promotes the activity of LCAT • With addition of cholesterol HDL particles becomes spherical
  13. 13. • HDL particles with cholesteryl esters trapped inside, enter the hepatocytes by a receptor mediate endocytosis. • In the liver cholesteryl esters are degraded to cholesterol. • Then it is utilized for the synthesis of bile acids and lipoproteins excreted into bile. • FUNCTION OF HDL: 1. Transport of cholesterol 2. Serves as reservoir of apoproteins
  14. 14. DISORDERS OF PLASMA LIPOPROTEINS • Mainly of two types • Primary : Due to genetic defects • Secondary : Due to some other diseases • Resulting in abnormal lipoprotein patterns • Hyper & Hypo lipoproteinemias
  15. 15. Hyperlipoproteinemias • Increase in one or more lipoproteins either by primary or secondary. TYPE INCREASE IN PROBABLE DEFECT RISK OF ATHEROSCLEROSIS SUGESTED TREATMENT I Chylomicrons Deficiency of LP lipase May incrase Low fat diet IIa LDL Deficiency of LDL receptors Very high in in coronary artery Low cholesterol fat diet, cholestyramine IIb LDL and VLDL Overproduction of Apo-B ------Do--------- ------Do------ III LDL Abnormality in apo-E Very high in peripheral vessels Low fat & caloric diet, clofibrate IV VLDL Overproduction of TG May or may not increases Low fat & caloric diet, niacin
  16. 16. Hypolipoproteinemias • Very low lipid levels 1. Familial hypobetalipoproteinemia: Due to impairment in synthesis of apo protein B Decrease in lipid up to 10-50% of normal values. This disorder is harmless and individual have healthy and long life.
  17. 17. 2. Abetalipoproteinemias: Rare and due to defect in synthesis of apo protein B • Total absence of b-lipoproteins in plasma, but accumulated into liver & intenstine • Impairment in physical growth & mental retardetion 3. Familial alpha-lipoprotein deficiency (tangier disease) • Plasma HDL is almost absent • Increased risk of atherosclerosis
  18. 18. FATTY LIVER • Normal lipid level in liver is around 5% • In certain condition lipids especially triacyl glycerisdes accumulated excessively into liver, resulting in fatty liver • In the normal liver kupffer cells contains lipids in droplet form, while in fatty liver they found in entire cytoplasm of hepatic cells • This causes impairment in metabolic function of liver • It occurs due to 1. Increased synthesis of triacylglycerols 2. Impairment in lipoprotein synthesis
  19. 19. FATTY ACID OXIDATION • β-oxidation “ Oxidation of fatty acids on the β-carbon atom.” • This results in the sequential removal of a two carbon fragment, acetyl CoA. • β-oxidation of fatty acids involves 3 stages: 1. Activation of f.a. occurring in the cytosol; 2. Transport of f.a. into mitochondria; 3. β-oxidation proper in the mitochondrial matrix.
  20. 20. STAGE-1 Activation of fatty acids occurring in the cytosol Fatty acid ATP Thiokinase Ppi Pyrophosphatase Acyladenylate CoASH AMP Acyl CoA 2Pi
  21. 21. STAGE-2 Transport of fatty acids into mitochondria Acyl CoA CYTOSOL Carnitine transport system MITOCHONDRION Acyl CoA
  22. 22. STAGE-3 β-oxidation proper in the mitochondrial matrix • Each cycle of β-oxidation, liberating a two carbon unitAcetyl CoA, occurs in a sequence of four reactions. 1. OXIDATION Acyl CoA Acyl CoA dehydrogenase Enoyl CoA 2. HYDRATION Enoyl CoA Enoyl CoA hydratase β-Hydroxyacyl CoA
  23. 23. 3. OXIDATION β-Hydroxyacyl CoA β-Hydroxyacyl CoA dehydrogenase β-Ketoacyl CoA 4. CLEAVAGE β-Ketoacyl CoA Thiolase Acyl CoA + Acetyl CoA
  24. 24. OXIDATION OF ODD CARBON CHAIN FATTY ACIDS
  25. 25. BETA OXIDATION OF FATTY ACIDS IN PEROXISOMES • Peroxisomes are organelles present in most eukayotic cells. • Beta oxidation occurs in a modified form in peroxisomes. • Acyl coA dehydrogenes leads to the formation of FADH2 as in beta oxidation.
  26. 26. REACTION IN BETA OXIDATION OF FATTY ACIDS IN PEROXISOMES • E-FADH2 +O2------------ E-FAD+H2O2 • H2O2--------------H2O +1/2 O2
  27. 27. KETONE BODIES • ACETONE • ACETO-ACETATE • β- HYDROXYBUTYRATE
  28. 28. BIOSYNTHESIS OF KETONE BODIES
  29. 29. Utilization • Ketone bodies transported from liver to various tissues. • Source of energy for the peripheral tissues such as skeletal muscle, cardiac muscle, renal cortex etc. • Utilization become more when glucose is in short supply to the tissues, as observed in starvation and diabetes mellitus. • Can meet 50-70% of the brain’s energy need.
  30. 30. METABOLISM OF K.B TO ACETYL CoA
  31. 31. • Concentration = 1mg/dl. • Ketonemia • Ketonuria • Ketosis • Ketosis is most commonly associated with starvation and severe uncontrolled diabetes mellitus.
  32. 32. Metabolism of Cholesterol By Kishor Sardesai
  33. 33. What is Metabolism?
  34. 34. Functions of cholesterol • Structural component of cell membrane. • Precursor for the synthesis of all other steroids in the body. • Essential ingredient in the structure of lipoproteins. • Fatty acids are transported to liver as cholesteryl esters for oxidation.
  35. 35. Biosynthesis of Cholesterol
  36. 36. Steps in Biosynthesis of Cholesterol 1. 2. 3. 4. 5. Synthesis of HMG Co A Formation of Mevalonate (6c) Production of isoprenoid units (5c) Synthesis of squalene (30c) Conversion of squalene to cholesterol (27c).
  37. 37. Biosynthesis of Cholesterol
  38. 38. CHOLESTEROL BIOSYNTHESIS PRESENT BY : GULAB YADAV
  39. 39. CHOLESTEROL BIOSYNTHESIS • 1gm/day synthesized in adults. • Contribution liver (50%),Intestine(15%), skin, Adrenal Cortex, reproductive tissue • Enzymes are present in cytosol • Acetyl CoA is the source of Carbon
  40. 40. Continue… • Production of one mole of Cholesterol 18 mole of Acetyl CoA 36 moles of ATP 16 moles of NADPH
  41. 41. Five Stages Of Cholesterol Synthesis 1. Synthesis of HMG CoA 2. Formation of Mevalonate (6C) 3. Production of Isoprenoid units (5C) 4. Synthesis of Squalene (30C) 5. Conversion of Squalene to cholesterol (27C)
  42. 42. STEPS OF CHOLESTEROL BIOSYNTHESIS WITH STRUCTURE
  43. 43. REGULATION OF CHOLESTEROL SYNTHESIS • Controlled by HMG CoA reductase (E.R.) 1.Feedback Control 2.Hormonal Regulation 3.Inhibition by drugs 4.Inhibition by Bile acids 5.Fasting Condition
  44. 44. 1. Feedback Control: • Increase in cellular concentration of cholesterol reduces enzyme synthesis. • Feedback Mechanism 2. Hormonal Regulation: • Enzymes in two interconvertible form • Influence of hormones (glucagon & glucocorticoids) results in formation of inactive HMG CoA reductase, thus decrease in cholesterol synthesis • Insulin & thyroxine increses cholesterol production by formation of active HMG CoA reductase
  45. 45. 3. Inhibition by drugs: • Compactin & lovastatin inhibits enzymes and reduces cholesterol synthesis (50-60%) 4. Bile acids 5. Fasting
  46. 46. DEGRADATION OF CHOLESTEROL • SYNTHESIS OF BILE ACIDS • SYNTHESIS OF STEROID HORMONS FROM CHOLESTEROL • SYNTHESIS OF VITAMIN D
  47. 47. SYNTHESIS OF BILE ACIDS Cholesterol NADPH+H+O2--------NADP 7-α-Hydroxylase 7-Hydroxycholesterol Cholic acid Chenodeoxycholic acid Taurine Glycine Taurine or Glycine Glycocholic acid Taurocholic acid INTESTINAL BACTERIA Tauro-or Glycochenodeoxycholic acid INTESTINAL BACTERIA Deoxycholic acid Lithocholic acid
  48. 48. SYNTHESIS OF STEROID HORMONES • • • • • GLUCOCORTICOIDS (e.g.Cortisol) MINERALOCORTICOIDS(e.g.Aldosterone) PROGESTINS(e.g.Progesterone) ANDROGENS(e.g.Testosterone) ESTROGENS(e.g.Estradiol)
  49. 49. SYNTHESIS OF VITAMIN D • 7-DEHYDROCHOLESTEROL SUN LIGHT SKIN • CHOLECALCIFEROL (VITAMIN D3)
  50. 50. Transport of cholesterol • Cholesterol is present in plasma lipoproteins in two forms: 1.70%-75% of it is in an esterified form with long chain fatty acids. 2.25%-30% as free cholesterol
  51. 51. Role of LCAT • HDL & the enzyme LCAT are responsible for transport and elimination of cholesterol from the body. • LCAT is synthesized by the liver,
  52. 52. Reaction catalyzed by LCAT • Phosphatidylcholine Lysophosphatidycholine Cholesterol Cholesterol ester
  53. 53. Plasma Cholesterol-Biomedical Importance • Healthy individuals: 150-200mg/dl • New born :less than100mg/dl, rises to about 150mg/dl within an year. • Women have relatively lower Plasma Cholesterol.
  54. 54. Major sources of liver cholesterol and its utilizations. Dietary cholesterol (500mg/day) Bile salts & Bile acids(250mg/day) Cholesterol pool (1000mg) Cholesterol lost in bile (500mg/day) Cholesterol synthesis in liver(500mg/day Cholesterol from extrahepatic tissues(variable) Lipoproteins
  55. 55. HYPERCHOLESTEROLEMIA Hypercholesterolemia (literally: high blood cholesterol) is the presence of high levels of cholesterol in the blood.  It is not a disease but a metabolic derangement that can be secondary to many diseases and can contribute to many forms of disease, most notably cardiovascular disease.
  56. 56. HYPERCHOLESTEROLEMIA is observed in many disorders like…  DIABETES MELLITUS  HYPOTHYROIDISM ( MYXOEDEMA)  OBSTRUCTIVE JAUNDICE  NEPHROTIC SYNDROME
  57. 57. CONTROL OF HYPERCHOLESTEROLEMIA  Consumption of PUFA  Dietary Cholesterol  Plant sterols  Dietary fiber  Avoiding high carbohydrate diet  Impact of Lifestyles  Moderate alcohol consumption  Use of Drugs
  58. 58. HYPOCHOLESTEROLEMIA Hypocholesterolemia is the presence of abnormally low (hypo-) levels of cholesterol in the blood (-emia).  Several genetic defects exist in the production of cholesterol from Acetyl CoA, resulting in hypocholesteremia.  Some disorders associated with Hypocholesterolemia are : HYPERTHYROIDISM HEMOLYTIC JAUNDICE

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