HDL代謝的生理學和病理學意義優(yōu)選課件

1、HDL and Coronary Heart DiseasePhysiology and Pathophysiology of HDL MetabolismHDL and Coronary Heart DiseaseStructure of HDL ParticleA-IA-IA-IIA-I, A-II = apolipoprotein A-I, A-II; CE = cholesteryl ester; TG = triglyceridesCETGStructure of HDL ParticleA-IA-Production of HDL by Liver and IntestineA-I

2、A-IA-IIA-I, A-II = apolipoprotein A-I, A-IILiverIntestineHDLHDLProduction of HDL by Liver andHDL Metabolism and Reverse Cholesterol TransportA-ILiverCECECEFCFCLCATFCBileSR-BIA-IABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I; CE = cholesteryl ester; FC = free cholesterol; LCAT = leci

3、thin:cholesterol acyltransferase; SR-BI = scavenger receptor class BIABC1MacrophageMature HDLNascent HDLHDL Metabolism and Reverse ChRole of CETP in HDL MetabolismA-ILiverCECEFCFCLCATFCBileSR-BIA-IABC1MacrophageCEBCETP = cholesteryl ester transfer proteinLDL = low-density lipoprotein LDLR = low-dens

4、ity lipoprotein receptorVLDL = very-low-density lipoproteinLDLRVLDL/LDLCETPMature HDLNascent HDLCESRAOxidationRole of CETP in HDL MetabolismRole of Hepatic Lipase and Lipoprotein Lipase in HDL MetabolismCM = chylomicron; CMR = chylomicron remnant; HDL = high-density lipoprotein; HL = hepatic lipase;

5、 IDL = intermediate-density lipoprotein; LPL = lipoprotein lipase; PL = phospholipase; TG = triglycerideBKidneyEndotheliumBTGCMR/IDLC-IICM/VLDLHLLPLA-ICE TGHDL2PLA-ICEHDL3PLPhospholipids and apolipoproteinsRole of Hepatic Lipase and LipPrimary (Genetic) Causes of Low HDL-CApoA-IComplete apoA-I defic

6、iencyApoA-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 hyperl

7、ipidemia with low HDL-CMetabolic syndromePrimary (Genetic) Causes of LoComplete ApoA-I DeficiencyMarkedly reduced HDL-C levels and absent apoA-ICutaneous xanthomas (some patients)Premature atherosclerotic vascular disease (some patients)Complete ApoA-I DeficiencyMarkApoA-I MutationsModest to marked

8、reduction in HDL-C and apoA-IRapid catabolism of apoA-ISystemic amyloidosis Premature atherosclerotic disease (rare)ApoA-I MutationsModest to markLCAT Deficiency and Fish-eye DiseaseBoth due to mutations in LCAT gene:LCAT deficiency completeFish-eye disease partialCommon to both types of LCAT defici

9、ency: 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 insufficiencyLCAT Deficiency and Fish-eye DHDL Metabolism in LCAT DeficiencyA-IFCFCLC

10、ATA-IABC1MacrophageRapid catabolismNascent HDLCEHDL Metabolism in LCAT DeficieTangier DiseaseAutosomal 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:Enlarge

11、d orange tonsilsHepatosplenomegalyPeripheral neuropathyTangier DiseaseAutosomal codomTangier Disease(Continued)Increased risk of premature atherosclerotic vascular diseasePathologic accumulation of cholesterol in macrophages and other cells of reticulo-endothelial systemHeterozygotes have moderately

12、 reduced HDL-C and apoA-I levels and increased risk of premature atherosclerotic vascular disease, but no tonsillar enlargement or hepatosplenomegalyTangier Disease(Continued)IncHDL Metabolism in Tangier DiseaseA-IFCFCA-IABC1MacrophageRapid catabolismLCATNascent HDLCEHDL Metabolism in Tangier DiseFa

13、milial HypoalphalipoproteinemiaDominant 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 diseaseFamilial HypoalphalipoproteineSecondary C

14、auses of Low HDL-CSmokingObesity (visceral fat)Very-low-fat dietHypertriglyceridemiaDrugsBeta-blockers Androgenic steroidsAndrogenic progestinsSecondary Causes of Low HDL-CSPrimary (Genetic) Causes of High HDL-CCETPCETP deficiencyHepatic lipaseHepatic lipase deficiencyUnknown genetic etiologyFamilia

15、l hyperalphalipoproteinemiaPrimary (Genetic) Causes of HiCETP DeficiencyAutosomal 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 evi

16、dence of protection against atherosclerosis; possible increased risk of premature atherosclerotic vascular diseaseCETP DeficiencyAutosomal co-doHDL Metabolism in CETP DeficiencyA-ICEFCFCLCATA-IMacrophageBDelayed catabolismCETPABC1HDLVLDL/LDLNascent HDLCEHDL Metabolism in CETP DeficieHepatic Lipase D

17、eficiencyAutosomal 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 pre

18、mature atherosclerotic vascular diseaseHepatic Lipase DeficiencyAutosHDL Metabolism in Hepatic Lipase DeficiencyA-ILiverA-ICE TGCEHLDelayed catabolismHDL2HDL3HDL Metabolism in Hepatic LipFamilial HyperalphalipoproteinemiaAutosomal dominant; molecular etiology unknownModest to marked elevations in HD

19、L-C and apoA-ISelective increased synthesis of apoA-I in some familiesAssociated with longevity and protection against atherosclerotic vascular disease in epidemiologic studiesFamilial HyperalphalipoproteinSecondary Causes of Increased HDL-CExtensive regular aerobic exerciseVery-high-fat dietRegular

20、 substantial alcohol intakeEstrogen replacement therapyDrugsPhenytoinSecondary Causes of Increased 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 pro

21、teins LCAT Lipoprotein lipase CETP Hepatic lipase PLTP Endothelial lipaseCellular and cell-surface proteins that influence HDL metabolism ABC1 SR-BIGenes Involved in HDL MetaboliGene Transfer of ApoA-I to Liver Induces Regression of Atherosclerosis in LDLR/ Mice012345BaselineAdnullAortic lesion (%)A

22、dhapoA-I* P 0.05Tangirala R et al. Circulation 1999;100:18161822Gene Transfer of ApoA-I to LivOverexpression 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