HDL代謝的生理學(xué)和病理學(xué)意義

HDLandCoronaryHeartDiseasePhysiologyandPathophysiologyofHDLMetabolismStructureofHDLParticleA-IA-IA-IIA-I,A-II=apolipoproteinA-I,A-II;

CE=cholesterylester;TG=triglyceridesCETGProductionofHDLbyLiverandIntestineA-IA-IA-IIA-I,A-II=apolipoproteinA-I,A-IILiverIntestineHDLHDLHDLMetabolismand

ReverseCholesterolTransportA-ILiverCECECEFCFCLCATFCBileSR-BIA-IABC1=ATP-bindingcassetteprotein1;A-I=apolipoproteinA-I;

CE=cholesterylester;FC=freecholesterol;

LCAT=lecithin:cholesterolacyltransferase;

SR-BI=scavengerreceptorclassBIABC1MacrophageMature

HDLNascent

HDLRoleofCETPinHDLMetabolismA-ILiverCECEFCFCLCATFCBileSR-BIA-IABC1MacrophageCEBCETP=cholesterylestertransferprotein

LDL=low-densitylipoprotein

LDLR=low-densitylipoproteinreceptor

VLDL=very-low-densitylipoproteinLDLRVLDL/LDLCETPMatureHDLNascentHDLCESRAOxidationRoleofHepaticLipaseandLipoproteinLipaseinHDLMetabolismCM=chylomicron;CMR=chylomicronremnant;HDL=high-densitylipoprotein;

HL=hepaticlipase;IDL=intermediate-densitylipoprotein;

LPL=lipoproteinlipase;PL=phospholipase;TG=triglycerideBKidneyEndotheliumBTGCMR/IDLC-IICM/VLDLHLLPLA-ICETGHDL2PLA-ICEHDL3PLPhospholipidsandapolipoproteinsPrimary(Genetic)CausesofLowHDL-CApoA-ICompleteapoA-IdeficiencyApoA-Imutations(eg,ApoA-IMilano)LCATCompleteLCATdeficiencyPartialLCATdeficiency(fish-eyedisease)ABC1TangierdiseaseHomozygousHeterozygousFamilialhypoalphalipoproteinemia(somefamilies)UnknowngeneticetiologyFamilialhypoalphalipoproteinemia(mostfamilies)FamilialcombinedhyperlipidemiawithlowHDL-CMetabolicsyndromeCompleteApoA-IDeficiencyMarkedlyreducedHDL-ClevelsandabsentapoA-ICutaneousxanthomas(somepatients)Prematureatheroscleroticvasculardisease

(somepatients)ApoA-IMutationsModesttomarkedreductioninHDL-CandapoA-IRapidcatabolismofapoA-ISystemicamyloidosisPrematureatheroscleroticdisease(rare)LCATDeficiencyandFish-eyeDiseaseBothduetomutationsinLCATgene:LCATdeficiency–completeFish-eyedisease–partialCommontobothtypesofLCATdeficiency:MarkedlyreducedHDL-CandapoA-IlevelsRapidcatabolismofapoA-IandapoA-IICornealarcusPrematureatheroscleroticvasculardisease(rare)UniquetocompleteLCATdeficiency:ProteinuriaandprogressiverenalinsufficiencyHDLMetabolisminLCATDeficiencyA-IFCFCLCATA-IABC1MacrophageRapidcatabolismNascentHDLCETangierDiseaseAutosomalcodominantdisorderduetomutationsinbothallelesofABC1geneExtremelymarkedreductioninHDL-CandapoA-IMarkedlyacceleratedcatabolismofapoA-IandapoA-IICholesterolaccumulation:EnlargedorangetonsilsHepatosplenomegalyPeripheralneuropathyTangierDisease

(Continued)IncreasedriskofprematureatheroscleroticvasculardiseasePathologicaccumulationofcholesterolinmacrophagesandothercellsofreticulo-endothelialsystemHeterozygoteshavemoderatelyreducedHDL-CandapoA-Ilevelsandincreasedriskofprematureatheroscleroticvasculardisease,butnotonsillarenlargementorhepatosplenomegalyHDLMetabolisminTangierDiseaseA-IFCFCA-IABC1MacrophageRapidcatabolismLCATNascentHDLCEFamilialHypoalphalipoproteinemiaDominantdisorder;duetomutationsinonealleleofABC1geneinsomefamilies,andofunknowngeneticetiologyinotherfamiliesModeratereductioninHDL-CandapoA-IIncreasedriskofprematureatheroscleroticvasculardiseaseSecondaryCausesofLowHDL-CSmokingObesity(visceralfat)Very-low-fatdietHypertriglyceridemiaDrugsBeta-blockersAndrogenicsteroidsAndrogenicprogestinsPrimary(Genetic)CausesofHighHDL-CCETPCETPdeficiencyHepaticlipaseHepaticlipasedeficiencyUnknowngeneticetiologyFamilialhyperalphalipoproteinemiaCETPDeficiencyAutosomalco-dominant;duetomutationsinbothallelesofCETPgeneMarkedlyelevatedlevelsofHDL-CandapoA-IDelayedcatabolismofHDLcholesterylesterandapoA-IHDLparticlesenlargedandenrichedincholesterylesterNoevidenceofprotectionagainstatherosclerosis;possibleincreasedriskofprematureatheroscleroticvasculardiseaseHDLMetabolisminCETPDeficiencyA-ICEFCFCLCATA-IMacrophageBDelayedcatabolismCETPABC1HDLVLDL/LDLNascentHDLCEHepaticLipaseDeficiencyAutosomalrecessive,duetomutationsinbothallelesofhepaticlipasegeneModestlyelevatedlevelsofHDL-CandapoA-IVariableelevationsintotalcholesterol,triglycerides,andlipoproteinremnantparticlesNoevidenceofprotectionagainstatherosclerosis;possibleincreasedriskofprematureatheroscleroticvasculardiseaseHDLMetabolisminHepatic

LipaseDeficiencyA-ILiverA-ICETGCEHLDelayedcatabolismHDL2HDL3FamilialHyperalphalipoproteinemiaAutosomaldominant;molecularetiologyunknownModesttomarkedelevationsinHDL-CandapoA-ISelectiveincreasedsynthesisofapoA-IinsomefamiliesAssociatedwithlongevityandprotectionagainstatheroscleroticvasculardiseaseinepidemiologicstudiesSecondaryCausesofIncreasedHDL-CExtensiveregularaerobicexerciseVery-high-fatdietRegularsubstantialalcoholintakeEstrogenreplacementtherapyDrugsPhenytoinGenesInvolvedinHDLMetabolism

PotentialTargetsforDevelopmentofNovelTherapiesforAtherosclerosis

HDL-associatedapolipoproteins —ApoA-I —ApoE —ApoA-IV

HDL-modifyingplasmaenzymesandtransferproteins —LCAT —Lipoproteinlipase —CETP —Hepaticlipase —PLTP —EndotheliallipaseCellularandcell-surfaceproteinsthatinfluenceHDLmetabolism —ABC1 —SR-BIGeneTransferofApoA-ItoLiverInducesRegressionofAtherosclerosisinLDLR–/–Mice012345BaselineAdnullAorticlesion(%)AdhapoA-I**P

0.05TangiralaRetal.Circulation1999;100:1816–1822OverexpressionofLCATPreventsDevelopmentofAtherosclerosisinTransgenicRabbits*P

<0.003LCAT=lecithin-cholesterolacyltransferase;Tg=transge