lipoprotein metabolism.pptx HDL METABOLISM, LDL METABOLIS, VLDL METABOLIS, CHYLOMICRON METABOLISM,

Lipoprotein introduction, their general characteristics, exogenous and endogenous metabolism focusing on chylomicron and vldl metabolism, ldl metabolism and HDL metabolism , reverse cholesterol transport.

1. Lipoprotein Metabolism

2. CONTENTS General structure of lipoprotein Classification of lipoproteins Apoproteins and their function Lipoprotein metabolism

3. Plasma lipids consist of Triacylglycerols (16%) Phospholipids (30%) Cholesterol (14%) Cholesteryl esters (36%) Unesterified long-chain fatty acids (4%).

4. Generalized structure of a plasma lipoprotein

5. Classification of Lipoproteins Chylomicrons Very low density lipoproteins (VLDL, or pre-β-lipoproteins) Low-density lipoproteins (LDL, or β-lipoproteins) 4. High-density lipoproteins (HDL, or α-lipoproteins)

6. Lipoproteins

7. Lipoproteins 1) Chylomicrons Derived from intestinal absorption of triacylglycerol and other lipids (Exogenous Pathway) 2) VLDL Derived from the liver for the export of triacylglycerol and other lipids (Endogenous Pathway)

8. 3) LDL Represents a final stage in the catabolism of VLDL Cholesterol transport from liver to peripheral tissues 4) HDL Cholesterol transport from peripheral tissues to liver “ Reverse cholesterol transport”

9. Apoproteins The protein part of lipoprotein is called apolipoprotein or apoprotein . Mainly synthesized in liver; but small quantities are produced from intestine…

10. Apo-A-I A component of HDL and ligand for HDL receptor. activates lecithin-cholesterol acyl transferase (LCAT) Apo-B-100 a component of VLDL and LDL ; it binds to LDL receptor on tissues synthesized in liver. Apo-B-48 the structural component of chylomicrons . synthesized in intestinal cells

11. Apo B-48 (48% of B-100) is formed from the same mRNA as apo B-100 after the introduction of a stop signal by an RNA editing enzyme.

12. GENERAL CHARACTERISTICS OF LIPOPROTEIN 15-20 1.063-1.121 40 60

13. Roles of apoproteins Form part of the structure of the lipoprotein e.g. apo B Enzyme cofactors e.g. C-II for lipoprotein lipase A-I for lecithin:cholesterol acyltransferase

14. Enzyme inhibitors e.g apo C-III for lipoprotein lipase Ligands for interaction with lipoprotein receptors in tissues e.g. apo B-100 for the LDL receptor, apo A-I for the HDL receptor

15. Enzymes and proteins involved in lipoprotein metabolism

16. Lipoprotein lipase An extracellular enzyme that is anchored by heparan sulfate to the endothelium of capillary walls of most tissues. Predominantly found in adipose tissue and cardiac and skeletal muscle whereas adult liver does not have this enzyme.

17. Lipoprotein lipase Activated by apo C-II on circulating lipoprotein particles. Hydrolyzes the triacylglycerol contained in these particles to yield fatty acids and glycerol.

18. Regulation of lipoprotein lipase activity Synthesis and transfer of lipoprotein lipase to the luminal surface of the capillary is stimulated by insulin Isomers of lipoprotein lipase have different Km values for triacylglycerol. The adipose enzyme has a high Km whereas heart muscle lipoprotein lipase has a low Km.

19. Hepatic lipase Present on the sinusoidal surface of liver cells. Plays some role in triacylglycerol degradation in CM remnant and VLDL remnant, and is particularly important in HDL metabolism

20. Hepatic lipase Hepatic lipase has a dual role : Acts as a ligand to facilitate remnant uptake Hydrolyzes remnant triacylglycerol and phospholipid .

21. LCAT Lecithin:Cholesterol AcylTransferase a plasma enzyme synthesized by the liver. LCAT binds to nascent HDL, and is activated by apo A-I. Esterification of cholesterol

22. ACAT Acyl CoA:Cholesterol AcylTransferase Present in tissues Excess of cholesterol activates ACAT and forms Cholesterol esters that is stored.

23. Cholesteryl Ester Transfer Protein (CETP) A protein, associated with HDL, is found in plasma of humans Facilitates transfer of cholesteryl ester from HDL to VLDL and Chylomicron in exchange for triacylglycerol.

24. Cholesterol Ester Transfer Protein (CETP)

25. Lipoprotein metabolism

26. Chylomicrons Density: < 0.95 g/mL Diameter : 90 – 1000 nm Exogenous or Dietary triglycerides Apo B-48 , apo A , apo E, apo C

27. Chylomicrons Found in chyle formed only by the lymphatic system draining the intestine . Responsible for the transport of dietary lipids mainly triglycerides from intestines to the adipose tissue for storage; and to muscle or heart for their energy needs.

28. Metabolism of chylomicron

29. Let us remember in 4 steps Formation of Nascent chylomicrons Then mature chylomicrons Then chylomicron remnants Uptake by Liver

30. Formation and secretion of chylomicron

31. 70-90% loss of TAG The resulting chylomicron remnant is about half the diameter of the parent chylomicron and is relatively enriched in cholesterol and cholesteryl esters because of the loss of triacylglycerol

32. Chylomicrons formed in intestinal mucosa They are rich in TAG [ diet ] and contain only Apo-B 48 Apo C-II and Apo E are added from HDL to Nascent CM  Mature CM Lipoprotein Lipase activated by Apo C-II, degrades TAG in CM Apo C-II, is returned to HDL Chylomicron remnants is formed Liver uptake the CM remnants with the help of Apo E, LDL receptor and LRP

33. Very low density lipoprotein (VLDL) Density: 0.95-1.006 g/mL Diameter : 30 – 90nm Endogenous triglycerides Apo B-100 , apo E, apo C-II/C-III Prebeta in electrophoresis

34. VLDL VLDL transports endogenous triacylglycerol synthesized in the liver to the peripheral tissues.

35. Assembly and release of VLDL

36. Metabolism of VLDL

37. Let us remember in 4 steps Formation of Nascent VLDL Then mature VLDL Then VLDL remnant/ IDL Formation of LDL

38. Idl has two fate 1] Taken up by liver 2] Covert in to LDL E Mature

39. Nascent VLDL from Liver [ Apo B-100] They are rich in TAG [ diet ] > Cholesterol Apo C-II and Apo E are added from HDL to Nascent VLDL  Mature Lipoprotein Lipase activated by Apo C-II, degrades TAG in Fatty acid and Glycerol Apo C-II, is returned to HDL VLDL remnants or IDL with Apo E and Apo B100 Loss of Apo E  Formation of LDL LDL are endocytosed by extrahepatic tissue and liver

40. Hepatic VLDL Secretion Is Related to Dietary & Hormonal Status Hepatic triacylglycerol synthesis provides the immediate stimulus for the formation and secretion of VLDL.

41. The fatty acids used are derived from two possible sources: synthesis within the liver from acetyl- CoA derived mainly from carbohydrate (2) uptake of free fatty acids from the circulation.

42. Factors that enhance both the synthesis of triacylglycerol and the secretion of VLDL by the liver include (1) The fed state rather than the starved state (2) The feeding of diets high in carbohydrate,

43. (3) High levels of circulating free fatty acids (4) Ingestion of ethanol (5) The presence of high concentrations of insulin and low concentrations of glucagon

44. Metabolism of LDL

45. After binding of LDL to its receptor LDL-receptor complex is internalized by endocytosis The vesicle containing LDL loses its clathrin coat Fuses with other similar vesicles Forming larger vesicles called endosomes Degraded by lysosomal acid hydrolases R elease free cholesterol, amino acids, fatty acids, and phospholipids Reutilized by the cell

46. Low Density Lipoprotein (LDL) Density: 1.019 - 1.063 g/mL Diameter: 20 -25nm Cholesterol and Cholesteryl esters ApoB-100 Beta in electrophoresis

47. LDL LDL particles contain much less triacylglycerol than their VLDL predecessors, and have a high concentration of cholesterol and cholesteryl esters. The primary function of LDL particles is to provide cholesterol to the peripheral tissues or return it to the liver.

48. Receptor-mediated endocytosis LDL receptors are negatively charged glycoproteins that are clustered in pits on cell membranes. The cytosolic side of the pit is coated with the protein clathrin , which stabilizes the shape of the pit.

49. After binding of LDL to its receptor LDL-receptor complex is internalized by endocytosis The vesicle containing LDL loses its clathrin coat Fuses with other similar vesicles Forming larger vesicles called endosomes

50. The pH of the endosome falls Allows separation of the LDL from its receptor The receptors then migrate to one side of the endosome , whereas the LDLs stay free within the lumen of the vesicle

51. The receptors can be recycled The lipoprotein remnants in the vesicle are transferred to lysosomes Degraded by lysosomal acid hydrolases R elease free cholesterol, amino acids, fatty acids, and phospholipids Reutilized by the cell

52. Uptake of chemically modified LDL by macrophage scavenger receptors Macrophages possess high levels of scavenger receptor activity, known as scavenger receptor class A (SR-A ), can bind a broad range of ligands , and mediate the endocytosis of chemically modified LDL in which the lipid components or apo B have been oxidized.

53. Unlike the LDL receptor, the scavenger receptor is not down-regulated in response to increased intracellular cholesterol. Cholesteryl esters accumulate in macrophages and cause their transformation into “foam” cells , which participatein the formation of atherosclerotic plaque.

54. Metabolism of HDL

55. HDL (High Density Lipoprotein) Density: 1.063-1.210 g/mL Diameter: 5-20 nm Major lipid components: Phospholipids and cholesterol Apolipoproteins : apoA -I , A-II, C-II, C-III and apoE Alpha in Electrophoresis

56. HDL Formed in blood by the addition of lipid to apo A-1 , an apolipoprotein made by the liver and intestine and secreted into blood. Apo A-1 accounts for about 70% of the apoproteins in HDL.

57. Functions of HDL A reservoir of apoproteins ( apo C-II and apo E) Reverse cholesterol transport HDL uptakes unesterified cholesterol from peripheral tissues and transport it to liver Esterification of cholesterol

58. Esterification of cholesterol lecithin:cholesterol acyltransferase

59. Metabolism of HDL

60. Nascent HDL by Liver and small intestine Nascent HDL or Discoidal Shape[ Apo A1, Phospholipid [ PL] , LCAT] Nascent HDL receives cholesterol from Peripheral tissue by ABCG1 & SRB1 Formation of HDL3 LCAT converts Cholesterol [ C ] to Cholesteryl esters [ CE] Formation of HDL2 [ excess CE in the core] HDL2 are taken by Liver [ SR B1 receptor ] and releases C, CE, PL inside liver HDL2 is converted to HDL3 again by the action of Hepatic Lipase Or gets converted into Pre B HDL [ by action of endothelial lipase] Pre B HDL receives Cholesterol from peripheral tissue by ABC A1

61. Reverse cholesterol transport Efflux of cholesterol from peripheral tissues to HDL Esterification of cholesterol Uptake of cholesterol ester by liver and conversion to bile acids.

62. Efflux of cholesterol from peripheral tissues to HDL Involves the ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). ABCG1 mediates the transport of cholesterol from cells to HDL ABCA1 preferentially promotes efflux to poorly lipidated particles such as preβ -HDL or apo A-1.

63. Esterification of cholesterol Lecithin: cholesterol acyltransferase (LCAT) activated by apo A-I esterification of cholesterol As cholesterol in HDL becomes esterified , it creates a concentration gradient and draws in cholesterol from tissues and from other lipoproteins.

64. Uptake of Cholesterolester by liver The class B scavenger receptor B1 (SR-B1) has been identified as an HDL receptor Has a dual role in HDL metabolism

65. SR-B1 1. In the liver and in steroidogenic tissues , Binds HDL via apo A-I Cholesteryl ester is selectively delivered to the cells 2. In the tissues , Mediates the efflux of cholesterol from the cells to HDL.

66. HDL cycle HDL3 , generated from discoidal HDL by the action of LCAT , accepts cholesterol from the tissues via the SR-B1 and the cholesterol is then esterified by LCAT, increasing the size of the particles to form the less dense HDL2 .

67. HDL cycle HDL3 is then reformed, either after selective delivery of cholesteryl ester to the liver via the SR-B1 or by hydrolysis of HDL2 phospholipid and triacylglycerol by hepatic lipase and endothelial lipase. This interchange of HDL2 and HDL3 is called the HDL cycle

68. HDL concentrations vary reciprocally with plasma triacylglycerol concentrations directly with the activity of lipoprotein lipase. This may be due to surplus surface constituents, eg , phospholipid and apo A-I, being released during hydrolysis of chylomicrons and VLDL and contributing toward the formation of preβ -HDL and discoidal HDL.

69. Clinical Note HDL2 concentrations are inversely related to the incidence of atherosclerosis, possibly because they reflect the efficiency of reverse cholesterol transport.

70. Preβ -HDL The most potent form of HDL inducing cholesterol efflux from the tissues. The formation of preβ -HDL may be due to Surplus surface constituents, eg , phospholipid and apo A-I, being released during hydrolysis of chylomicrons and VLDL. Free apo A-I released during the process of HDL cycle associating with minimum amount of PLs & cholesterol

71. HDLc (HDL1) Found in the blood of diet-induced hypercholesterolemic animals. It is rich in cholesterol, and its sole apolipoprotein is apo E.

72. Lipoprotein (a) Identical in structure to an LDL particle. Presence of an additional apolipoprotein molecule, apo (a) Covalently linked at a single site to apo B-100.

73. Associated with an increased risk of coronary heart disease. Apo(a) is structurally homologous to plasminogen . Elevated Lp (a) competes with plasminogen for binding to fibrin. Slows the breakdown of blood clots that trigger heart attacks

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