HDL代谢的生理学和病理学意义课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,HDL and Coronary Heart Disease,Physiology and Pathophysiology of HDL Metabolism,HDL and Coronary Heart Disease,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,Structure of HDL ParticleA-IA-,Production of HDL by Liver and Intestine,A-I,A-I,A-II,A-I, A-II = apolipoprotein A-I, A-II,Liver,Intestine,HDL,HDL,Production of HDL by Liver and,HDL Metabolism and Reverse Cholesterol Transport,A-I,Liver,CE,CE,CE,FC,FC,LCAT,FC,Bile,SR-,B,I,A-I,ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I; CE = cholesteryl ester; FC = free cholesterol; LCAT = lecithin:cholesterol acyltransferase; SR-,B,I = scavenger receptor class BI,ABC1,Macrophage,Mature HDL,Nascent HDL,HDL Metabolism and Reverse Ch,Role of CETP in HDL Metabolism,A-I,Liver,CE,CE,FC,FC,LCAT,FC,Bile,SR-,B,I,A-I,ABC1,Macrophage,CE,B,CETP = cholesteryl ester transfer proteinLDL = low-density lipoprotein LDLR = low-density lipoprotein receptorVLDL = very-low-density lipoprotein,LDLR,VLDL/LDL,CETP,Mature HDL,Nascent HDL,CE,SRA,Oxidation,Role of CETP in HDL Metabolism,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; TG = triglyceride,B,Kidney,Endothelium,B,TG,CMR/IDL,C-II,CM/VLDL,HL,LPL,A-I,CE,TG,HDL,2,PL,A-I,CE,HDL,3,PL,Phospholipids and apolipoproteins,Role of Hepatic Lipase and Lip,Primary (Genetic) Causes of Low HDL-C,ApoA-I,Complete apoA-I deficiency,ApoA-I mutations (eg, ApoA-I,Milano,),LCAT,Complete LCAT deficiency,Partial LCAT deficiency (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,Primary (Genetic) Causes of Lo,Complete ApoA-I Deficiency,Markedly reduced HDL-C levels and absent apoA-I,Cutaneous xanthomas (some patients),Premature atherosclerotic vascular disease (some patients),Complete ApoA-I DeficiencyMark,ApoA-I Mutations,Modest to marked reduction in HDL-C and apoA-I,Rapid catabolism of apoA-I,Systemic amyloidosis,Premature atherosclerotic disease (rare),ApoA-I MutationsModest to mark,LCAT Deficiency and 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 complete LCAT deficiency:,Proteinuria and progressive renal insufficiency,LCAT Deficiency and Fish-eye D,HDL Metabolism in LCAT Deficiency,A-I,FC,FC,LCAT,A-I,ABC1,Macrophage,Rapid catabolism,Nascent HDL,CE,HDL Metabolism in LCAT Deficie,Tangier Disease,Autosomal codominant disorder due to mutations in both alleles of ABC1 gene,Extremely marked reduction in HDL-C and apoA-I,Markedly accelerated catabolism of apoA-I and apoA-II,Cholesterol accumulation:,Enlarged orange tonsils,Hepatosplenomegaly,Peripheral neuropathy,Tangier DiseaseAutosomal codom,Tangier Disease(Continued),Increased risk of premature atherosclerotic vascular disease,Pathologic accumulation of cholesterol in macrophages 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,Tangier Disease(Continued)Inc,HDL Metabolism in Tangier Disease,A-I,FC,FC,A-I,ABC1,Macrophage,Rapid catabolism,LCAT,Nascent HDL,CE,HDL Metabolism in Tangier Dise,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,Familial Hypoalphalipoproteine,Secondary Causes of Low HDL-C,Smoking,Obesity (visceral fat),Very-low-fat diet,Hypertriglyceridemia,Drugs,Beta-blockers,Androgenic steroids,Androgenic progestins,Secondary Causes of Low HDL-CS,Primary (Genetic) Causes of High HDL-C,CETP,CETP deficiency,Hepatic lipase,Hepatic lipase deficiency,Unknown genetic etiology,Familial hyperalphalipoproteinemia,Primary (Genetic) Causes of Hi,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 atherosclerosis; possible increased risk of premature atherosclerotic vascular disease,CETP DeficiencyAutosomal co-do,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,HDL Metabolism in CETP Deficie,Hepatic Lipase Deficiency,Autosomal recessive, due to mutations in both alleles of hepatic lipase 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,Hepatic Lipase DeficiencyAutos,HDL Metabolism in Hepatic Lipase Deficiency,A-I,Liver,A-I,CE,TG,CE,HL,Delayed catabolism,HDL,2,HDL,3,HDL Metabolism in Hepatic Lip,Familial Hyperalphalipoproteinemia,Autosomal dominant; molecular etiology unknown,Modest to marked elevations in HDL-C and apoA-I,Selective increased synthesis of apoA-I in some families,Associated with longevity and protection against atherosclerotic vascular disease in epidemiologic studies,Familial Hyperalphalipoprotein,Secondary Causes of Increased HDL-C,Extensive regular aerobic exercise,Very-high-fat diet,Regular substantial alcohol intake,Estrogen replacement therapy,Drugs,Phenytoin,Secondary Causes of Increased,Genes Involved in HDL Metabolism,Potential Targets for Development of Novel Therapies for Atherosclerosis,HDL-associated apolipoproteins, ApoA-I ApoE, ApoA-IV,HDL-modifying plasma enzymes and transfer proteins, LCAT Lipoprotein lipase, CETP Hepatic lipase, PLTP Endothelial lipase,Cellular and cell-surface proteins that influence HDL metabolism, ABC1 SR-,BI,Genes Involved in HDL Metaboli,Gene Transfer of ApoA-I to Liver Induces Regression of Atherosclerosis in LDLR,/,Mice,0,1,2,3,4,5,Baseline,Adnull,Aortic lesion (%),AdhapoA-I,*,*,P, 0.05,Tangirala R et al.,Circulation,1999;100:18161822,Gene Transfer of ApoA-I to Liv,Overexpression of LCAT Prevents Development of Atherosclerosis in Transgenic Rabbits,*,P, 0.003,LCAT = lecithin-cholesterol acyltransferase; Tg = transgenic,Hoeg JM et al.,Proc Natl Acad Sci U S A,. 1996;93:1144811453,Copyright 1996 National Academy of Sciences, USA.,0,10,20,30,40,50,Control,LCAT Tg,Atherosclerotic surface area (%),*,Overexpression of LCAT Prevent,Summary,HDL metabolism is complex,HDL-C and apoA-I levels are determined by both production and catabolic rates,Rates of reverse cholesterol transport cannot be determined solely by steady-state levels of HDL-C and apoA-I,Effect of genetic defects or of interventions that alter HDL metabolism on atherosclerosis depends on specific metabolic effects on HDL,Genes and proteins involved in HDL metabolism are potential targets for development of novel therapeutic strategies for atherosclerosis,SummaryHDL metabolism is compl,HDL代谢的生理学和病理学意义课件,