1、Physiology and Pathophysiology of HDL MetabolismA-IA-IA-IIA-I,A-II=apolipoprotein A-I,A-II;CE=cholesteryl ester;TG=triglyceridesCETGA-IA-IA-IIA-I,A-II=apolipoprotein A-I,A-IILiverIntestineHDLHDLA-ILiverCECECEFCFCLCATFCBileSR-BIA-IABC1=ATP-binding cassette protein 1;A-I=apolipoprotein A-I;CE=choleste
2、ryl ester;FC=free cholesterol;LCAT=lecithin:cholesterol acyltransferase;SR-BI=scavenger receptor class BIABC1MacrophageMature HDLNascent HDLA-ILiverCECEFCFCLCATFCBileSR-BIA-IABC1MacrophageCEBCETP=cholesteryl ester transfer proteinLDL=low-density lipoprotein LDLR=low-density lipoprotein receptorVLDL=
3、very-low-density lipoproteinLDLRVLDL/LDLCETPMature HDLNascent HDLCESRAOxidationCM=chylomicron;CMR=chylomicron remnant;HDL=high-density lipoprotein;HL=hepatic lipase;IDL=intermediate-density lipoprotein;LPL=lipoprotein lipase;PL=phospholipase;TG=triglycerideBKidneyEndotheliumBTGCMR/IDLC-IICM/VLDLHLLP
4、LA-ICE TGHDL2PLA-ICEHDL3PLPhospholipids and apolipoproteinsnApoA-InComplete apoA-I deficiencynApoA-I mutations(eg,ApoA-IMilano)nLCATnComplete LCAT deficiencynPartial LCAT deficiency(fish-eye disease)nABC1nTangier diseasenHomozygousnHeterozygous nFamilial hypoalphalipoproteinemia(some families)nUnkno
5、wn genetic etiologynFamilial hypoalphalipoproteinemia(most families)nFamilial combined hyperlipidemia with low HDL-CnMetabolic syndromenMarkedly reduced HDL-C levels and absent apoA-InCutaneous xanthomas(some patients)nPremature atherosclerotic vascular disease(some patients)nModest to marked reduct
6、ion in HDL-C and apoA-InRapid catabolism of apoA-InSystemic amyloidosis nPremature atherosclerotic disease(rare)nBoth due to mutations in LCAT gene:nLCAT deficiency completenFish-eye disease partialnCommon to both types of LCAT deficiency:nMarkedly reduced HDL-C and apoA-I levelsnRapid catabolism of
7、 apoA-I and apoA-IInCorneal arcusnPremature atherosclerotic vascular disease(rare)nUnique to complete LCAT deficiency:nProteinuria and progressive renal insufficiencyA-IFCFCLCATA-IABC1MacrophageRapid catabolismNascent HDLCEnAutosomal codominant disorder due to mutations in both alleles of ABC1 genen
8、Extremely marked reduction in HDL-C and apoA-I nMarkedly accelerated catabolism of apoA-I and apoA-IInCholesterol accumulation:nEnlarged orange tonsilsnHepatosplenomegalynPeripheral neuropathynIncreased risk of premature atherosclerotic vascular diseasenPathologic accumulation of cholesterol in macr
9、ophages and other cells of reticulo-endothelial systemnHeterozygotes have moderately reduced HDL-C and apoA-I levels and increased risk of premature atherosclerotic vascular disease,but no tonsillar enlargement or hepatosplenomegalyA-IFCFCA-IABC1MacrophageRapid catabolismLCATNascent HDLCEnDominant d
10、isorder;due to mutations in one allele of ABC1 gene in some families,and of unknown genetic etiology in other familiesnModerate reduction in HDL-C and apoA-InIncreased risk of premature atherosclerotic vascular diseasenSmokingnObesity(visceral fat)nVery-low-fat dietnHypertriglyceridemianDrugsnBeta-b
11、lockers nAndrogenic steroidsnAndrogenic progestinsnCETPnCETP deficiencynHepatic lipasenHepatic lipase deficiencynUnknown genetic etiologynFamilial hyperalphalipoproteinemianAutosomal co-dominant;due to mutations in both alleles of CETP genenMarkedly elevated levels of HDL-C and apoA-InDelayed catabo
12、lism of HDL cholesteryl ester and apoA-InHDL particles enlarged and enriched in cholesteryl esternNo evidence of protection against atherosclerosis;possible increased risk of premature atherosclerotic vascular diseaseA-ICEFCFCLCATA-IMacrophageBDelayed catabolismCETPABC1HDLVLDL/LDLNascent HDLCEnAutos
13、omal recessive,due to mutations in both alleles of hepatic lipase genenModestly elevated levels of HDL-C and apoA-InVariable elevations in total cholesterol,triglycerides,and lipoprotein remnant particlesnNo evidence of protection against atherosclerosis;possible increased risk of premature atherosc
14、lerotic vascular diseaseA-ILiverA-ICE TGCEHLDelayed catabolismHDL2HDL3nAutosomal dominant;molecular etiology unknownnModest to marked elevations in HDL-C and apoA-InSelective increased synthesis of apoA-I in some familiesnAssociated with longevity and protection against atherosclerotic vascular dise
15、ase in epidemiologic studiesnExtensive regular aerobic exercisenVery-high-fat dietnRegular substantial alcohol intakenEstrogen replacement therapynDrugsnPhenytoinn HDL-associated apolipoproteins ApoA-I ApoE ApoA-IVn HDL-modifying plasma enzymes and transfer proteins LCAT Lipoprotein lipase CETP Hepa
16、tic lipase PLTP Endothelial lipasenCellular and cell-surface proteins that influence HDL metabolism ABC1 SR-BI012345BaselineAdnullAortic lesion(%)AdhapoA-I*P 0.05Tangirala R et al.Circulation 1999;100:18161822*P 0.003LCAT=lecithin-cholesterol acyltransferase;Tg=transgenicHoeg JM et al.Proc Natl Acad
17、 Sci U S A.1996;93:1144811453Copyright 1996 National Academy of Sciences,USA.01020304050ControlLCAT TgAtherosclerotic surface area(%)*nHDL metabolism is complexnHDL-C and apoA-I levels are determined by both production and catabolic ratesnRates of reverse cholesterol transport cannot be determined s
18、olely by steady-state levels of HDL-C and apoA-InEffect of genetic defects or of interventions that alter HDL metabolism on atherosclerosis depends on specific metabolic effects on HDL nGenes and proteins involved in HDL metabolism are potential targets for development of novel therapeutic strategies for atherosclerosis谢谢您的聆听与观看THANK YOU FOR YOUR GUIDANCE.感谢阅读！为了方便学习和使用，本文档的内容可以在下载后随意修改，调整和打印。欢迎下载！汇报人：XXX日期：20XX年XX月XX日
