Lipoprotein Overview

Transcription

1 Lipoprotein Overview

2 Lipoprotein Particle Structure Apolipoprotein Apolipoprotein POLAR SURFACE COAT Phospholipid Free cholesterol NONPOLAR LIPID CORE Cholesterol Ester Triglyceride Apolipoprotein

3 Density (g/ml) Lipoprotein Subclasses 0.95 VLDL Chylomicrons IDL 1.02 LDL Chylomicron Remnants HDL 3 HDL 2 Lp(a) Diameter (nm)

4 Lipoprotein Classes Chylomicrons, VLDL, and their catabolic remnants > 30 nm LDL nm HDL 9 15 nm D<1.006 g/ml D= g/ml D= g/ml Doi H et al. Circulation 2000;102: ; Colome C et al. Atherosclerosis 2000; 149: ; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15: Lipids Online

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7 What do lipoproteins do? Serve to transport lipid-soluble compounds between tissues Substrates for energy metabolism (TG) Essential components for cells (PL, UC) Precursors for hormones Precursors for eicosanoids Lipid soluble vitamins Precursors for bile acids

8 The Players - Apolipoproteins Apo AI (liver, small intestine) Structural; activator of lecithin:cholesterol acyltransferase (LCAT) Apo AII (liver) Structural; inhibitor of hepatic lipase; component of ligand for HDL binding Apo A-IV (small intestine) Activator of LCAT; modulator of lipoprotein lipase (LPL) Apo A-V (liver) Direct functional role is unknown; regulates TG levels.

9 Apolipoproteins Apo B-100 (liver) Structural; synthesis of VLDL; ligand for LDLreceptor Apo B-48 (small intestine) Structural; synthesis of chylomicrons; derived from apo B-100 mrna following specific mrna editing Apo E (liver, macrophages, brain) Ligand for apoe receptor; mobilization of cellular cholesterol

10 Apolipoproteins Apo C-I (liver) Activator of LCAT, inhibitor of hepatic TGRL uptake Apo C-II (liver) Activator of LPL, inhibitor of hepatic TGRL uptake Apo C-III (liver) Inhibitor of LPL, inhibitor of hepatic TGRL uptake

11 Lipoprotein Metabolism Exogenous/chylomicron pathway (dietary fat) Endogenous pathway (lipids synthesized by the liver) HDL metabolism (apolipoprotein transfer, cholesteryl ester transfer, reverse cholesterol transport

12 Lipoprotein Metabolism Exogenous/chylomicron pathway (dietary fat) Endogenous pathway (lipids synthesized by the liver) HDL metabolism (apolipoprotein transfer, cholesteryl ester transfer, reverse cholesterol transport

13 Rutas Metabólica de las Lipoproteínas en Humanos

14 Lipoprotein Metabolism Exogenous/chylomicron pathway (dietary fat) Endogenous pathway (lipids synthesized by the liver) HDL metabolism (apolipoprotein transfer, cholesteryl ester transfer, reverse cholesterol transport

15 TG Rich: VLDL Surface Monolayer Phospholipids (12%) Free Cholesterol (14%) Protein (4%) Hydrophobic Core Triglyceride (65%) Cholesteryl Esters (8%) Cholesterol and Atherosclerosis, Grundy)

16 VLDL Biogenesis Microsomal TG transfer protein (MTP) Facilitates the translocation, folding of apob and addition of lipids to lipid binding domains TG and cholesterol are synthesized in the liver as VLDL which contains apob- 100 Cholesterol and Atherosclerosis, Grundy)

17 VLDL Metabolism Apo C s and apoe and cholesteryl ester are acquired from HDL in circulation Cholesterol and Atherosclerosis, Grundy)

18 Fatty Acid Transport ApoC-II activates lipoprotein lipase which catalyses the hydrolysis of TG Cholesterol and Atherosclerosis, Grundy)

19 VLDL Metabolism Apolipoproteins are transferred back to HDL The end product is a VLDL remnant (IDL) Cholesterol and Atherosclerosis, Grundy)

20 CE Rich: LDL Surface Monolayer Phospholipids (25%) Free Cholesterol (15%) Protein (22%) Hydrophobic Core Triglyceride (5%) Cholesteryl Esters (35%) Cholesterol and Atherosclerosis, Grundy)

21 LDL Metabolism LDL is removed by apob100 receptors which are mainly expressed in the liver Hepatic Lipase Cholesteryl ester transfer protein Cholesterol and Atherosclerosis, Grundy)

22 LDL Cellular Metabolism LDL are taken up by the LDL Receptor into clathrin-coated pits Cholesterol and Atherosaclerosis, Grundy)

23 LDL Cellular Metabolism LDL dissociates from the receptor; the receptor recycles to the membrane Cholesterol and Atherosaclerosis, Grundy)

24 LDL Cellular Metabolism In the lysosome, lipids are deseterified; proteins are hydrolyzed Cholesterol and Atherosaclerosis, Grundy)

25 LDL Cellular Metabolism Increase in free cholesterol regulates decrease cholesterol synthesis and uptake; increase cholesterol esterification Cholesterol and Atherosaclerosis, Grundy)

26 Lipoprotein Metabolism Exogenous/chylomicron pathway (dietary fat) Endogenous pathway (lipids synthesized by the liver) HDL metabolism (apolipoprotein transfer, cholesteryl ester transfer, reverse cholesterol transport

27 CE Rich: HDL Surface Monolayer Phospholipids (25%) Free Cholesterol (7%) Protein (45%) Hydrophobic Core Triglyceride (5%) Cholesteryl Esters (18%) Cholesterol and Atherosclerosis, Grundy)

28 HDL Subpopulations Particle Shape Apolipoprotein Composition Discoidal Spherical A-I HDL A-I/A-II HDL A-II HDL Particle Size Lipid Composition TG, CE, and PL HDL 2b HDL 2a HDL 3a HDL 3b HDL 3c Rye KA et al. Atherosclerosis 1999;145: Lipids Online

29 HDL Maturation HDL is secreted in a discoidal form from the liver and gut. As it acquires cholesterol from tissues in the circulation, it matures into a spherical form through the action of lecithin:cholesterol acyl transferase Cholesterol and Atherosclerosis, Grundy)

30 HDL Metabolism Nascent HDL (lipid-poor apoa-i) is produced by the liver and intestine

31 Cholesterol and Atherosaclerosis, Grundy) Cholesterol Recycling