HDL代谢的生理学和病理学意义(ENGLISH).ppt

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,CETG,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,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 receptor 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 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 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,HDL2,PL,A-I,CE,HDL3,PL,Phospholipids and apolipoproteins,Primary(Genetic)Causes of Low HDL-C,ApoA-IComplete apoA-I deficiencyApoA-I mutations(eg,ApoA-IMilano)LCATComplete LCAT deficiencyPartial LCAT deficiency(fish-eye disease)ABC1Tangier diseaseHomozygousHeterozygous Familial hypoalphalipoproteinemia(some families)Unknown genetic etiologyFamilial hypoalphalipoproteinemia(most families)Familial combined hyperlipidemia with low HDL-CMetabolic syndrome,Complete ApoA-I Deficiency,Markedly reduced HDL-C levels and absent apoA-ICutaneous xanthomas(some patients)Premature atherosclerotic vascular disease(some patients),ApoA-I Mutations,Modest to marked reduction in HDL-C and apoA-IRapid catabolism of apoA-ISystemic amyloidosis Premature atherosclerotic disease(rare),LCAT Deficiency and Fish-eye Disease,Both due to mutations in LCAT gene:LCAT deficiency completeFish-eye disease partialCommon to both types of LCAT deficiency:Markedly reduced HDL-C and apoA-I levelsRapid catabolism of apoA-I and apoA-IICorneal arcusPremature atherosclerotic vascular disease(rare)Unique to 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 geneExtremely marked reduction in HDL-C and apoA-I Markedly accelerated catabolism of apoA-I and apoA-IICholesterol accumulation:Enlarged orange tonsilsHepatosplenomegalyPeripheral neuropathy,Tangier Disease(Continued),Increased risk of premature atherosclerotic vascular diseasePathologic accumulation of cholesterol in macrophages and other cells of reticulo-endothelial systemHeterozygotes 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 catabolism,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 familiesModerate reduction in HDL-C and apoA-IIncreased risk of premature atherosclerotic vascular disease,Secondary Causes of Low HDL-C,SmokingObesity(visceral fat)Very-low-fat dietHypertriglyceridemiaDrugsBeta-blockers Androgenic steroidsAndrogenic progestins,Primary(Genetic)Causes of High HDL-C,CETPCETP deficiencyHepatic lipaseHepatic lipase deficiencyUnknown genetic etiologyFamilial hyperalphalipoproteinemia,CETP Deficiency,Autosomal co-dominant;due to mutations in both alleles of CETP geneMarkedly elevated levels of HDL-C and apoA-IDelayed catabolism of HDL cholesteryl ester and apoA-IHDL particles enlarged and enriched in cholesteryl esterNo evidence of protection against atherosclerosis;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 lipase geneModestly elevated levels of HDL-C and apoA-IVariable elevations in total cholesterol,triglycerides,and lipoprotein remnant particlesNo 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 Hyperalphalipoproteinemia,Autosomal dominant;molecular etiology unknownModest to marked elevations in HDL-C and apoA-ISelective increased synthesis of apoA-I in some familiesAssociated with longevity and protection against atherosclerotic vascular disease in epidemiologic studies,Secondary Causes of Increased HDL-C,Extensive regular aerobic exerciseVery-high-fat dietRegular substantial alcohol intakeEstrogen replacement therapyDrugsPhenytoin,Genes Involved in HDL MetabolismPotential 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 lipaseCellular and cell-surface proteins that influence HDL metabolism ABC1 SR-BI,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 0.05Tangirala R et al.Circulation 1999;100:18161822,Overexpression of LCAT Prevents Development of Atherosclerosis in Transgenic Rabbits,*P 0.003LCAT=lecithin-cholesterol acyltransferase;Tg=transgenicHoeg JM et al.Proc Natl Acad Sci U S A.1996;93:1144811453Copyright 1996 National Academy of Sciences,USA.,0,10,20,30,40,50,Control,LCAT Tg,Atherosclerotic surface area(%),*,Summary,HDL metabolism is complexHDL-C and apoA-I levels are determined by both production and catabolic ratesRates of reverse cholesterol transport cannot be determined solely by steady-state levels of HDL-C and apoA-IEffect 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,