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1、HDL and Coronary Heart Disease,Physiology and Pathophysiology of HDL Metabolism,Structure of HDL Particle,A-I,A-I,A-II,A-I, A-II = apolipoprotein A-I, A-II; CE = cholesteryl ester; TG = triglycerides,CE TG,Production of HDL by Liver and Intestine,A-I,A-I,A-II,A-I, A-II = apolipoprotein A-I, A-II,Liv
2、er,Intestine,HDL,HDL,HDL Metabolism and Reverse Cholesterol Transport,A-I,Liver,CE,CE,CE,FC,FC,LCAT,FC,Bile,SR-BI,A-I,ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I; CE = cholesteryl ester; FC = free cholesterol; LCAT = lecithin:cholesterol acyltransferase; SR-BI = scavenger recepto
3、r class BI,ABC1,Macrophage,Mature HDL,Nascent HDL,Role of CETP in HDL Metabolism,A-I,Liver,CE,CE,FC,FC,LCAT,FC,Bile,SR-BI,A-I,ABC1,Macrophage,CE,B,CETP = cholesteryl ester transfer protein LDL = low-density lipoprotein LDLR = low-density lipoprotein receptor VLDL = very-low-density lipoprotein,LDLR,
4、VLDL/LDL,CETP,Mature HDL,Nascent HDL,CE,SRA,Oxidation,Role of Hepatic Lipase and Lipoprotein Lipase in HDL Metabolism,CM = chylomicron; CMR = chylomicron remnant; HDL = high-density lipoprotein; HL = hepatic lipase; IDL = intermediate-density lipoprotein; LPL = lipoprotein lipase; PL = phospholipase
5、; TG = triglyceride,B,Kidney,Endothelium,B,TG,CMR/IDL,C-II,CM/VLDL,HL,LPL,A-I,CE TG,HDL2,PL,A-I,CE,HDL3,PL,Phospholipids and apolipoproteins,Primary (Genetic) Causes of Low HDL-C,ApoA-I Complete apoA-I deficiency ApoA-I mutations (eg, ApoA-IMilano) LCAT Complete LCAT deficiency Partial LCAT deficien
6、cy (fish-eye disease) ABC1 Tangier disease Homozygous Heterozygous Familial hypoalphalipoproteinemia (some families) Unknown genetic etiology Familial hypoalphalipoproteinemia (most families) Familial combined hyperlipidemia with low HDL-C Metabolic syndrome,Complete ApoA-I Deficiency,Markedly reduc
7、ed HDL-C levels and absent apoA-I Cutaneous xanthomas (some patients) Premature atherosclerotic vascular disease (some patients),ApoA-I Mutations,Modest to marked reduction in HDL-C and apoA-I Rapid catabolism of apoA-I Systemic amyloidosis Premature atherosclerotic disease (rare),LCAT Deficiency an
8、d Fish-eye Disease,Both due to mutations in LCAT gene: LCAT deficiency complete Fish-eye disease partial Common to both types of LCAT deficiency: Markedly reduced HDL-C and apoA-I levels Rapid catabolism of apoA-I and apoA-II Corneal arcus Premature atherosclerotic vascular disease (rare) Unique to
9、complete LCAT deficiency: Proteinuria and progressive renal insufficiency,HDL Metabolism in LCAT Deficiency,A-I,FC,FC,LCAT,A-I,ABC1,Macrophage,Rapid catabolism,Nascent HDL,CE,Tangier Disease,Autosomal codominant disorder due to mutations in both alleles of ABC1 gene Extremely marked reduction in HDL
10、-C and apoA-I Markedly accelerated catabolism of apoA-I and apoA-II Cholesterol accumulation: Enlarged orange tonsils Hepatosplenomegaly Peripheral neuropathy,Tangier Disease (Continued),Increased risk of premature atherosclerotic vascular disease Pathologic accumulation of cholesterol in macrophage
11、s and other cells of reticulo-endothelial system Heterozygotes have moderately reduced HDL-C and apoA-I levels and increased risk of premature atherosclerotic vascular disease, but no tonsillar enlargement or hepatosplenomegaly,HDL Metabolism in Tangier Disease,A-I,FC,FC,A-I,ABC1,Macrophage,Rapid ca
12、tabolism,LCAT,Nascent HDL,CE,Familial Hypoalphalipoproteinemia,Dominant disorder; due to mutations in one allele of ABC1 gene in some families, and of unknown genetic etiology in other families Moderate reduction in HDL-C and apoA-I Increased risk of premature atherosclerotic vascular disease,Second
13、ary Causes of Low HDL-C,Smoking Obesity (visceral fat) Very-low-fat diet Hypertriglyceridemia Drugs Beta-blockers Androgenic steroids Androgenic progestins,Primary (Genetic) Causes of High HDL-C,CETP CETP deficiency Hepatic lipase Hepatic lipase deficiency Unknown genetic etiology Familial hyperalph
14、alipoproteinemia,CETP Deficiency,Autosomal co-dominant; due to mutations in both alleles of CETP gene Markedly elevated levels of HDL-C and apoA-I Delayed catabolism of HDL cholesteryl ester and apoA-I HDL particles enlarged and enriched in cholesteryl ester No evidence of protection against atheros
15、clerosis; possible increased risk of premature atherosclerotic vascular disease,HDL Metabolism in CETP Deficiency,A-I,CE,FC,FC,LCAT,A-I,Macrophage,B,Delayed catabolism,CETP,ABC1,HDL,VLDL/LDL,Nascent HDL,CE,Hepatic Lipase Deficiency,Autosomal recessive, due to mutations in both alleles of hepatic lip
16、ase gene Modestly elevated levels of HDL-C and apoA-I Variable elevations in total cholesterol, triglycerides, and lipoprotein remnant particles No evidence of protection against atherosclerosis; possible increased risk of premature atherosclerotic vascular disease,HDL Metabolism in Hepatic Lipase Deficiency,A-I,Liver,A-I,CE TG,CE,HL,Delayed catabolism,HDL2,HDL3,Familial Hyperalphalipoproteinemi
