胆固醇代谢平衡调控讲课稿

胆固醇代谢平衡调控胆固醇的生物学功能PhospholipidModifiedfromMolecularBiologyoftheCell,1994SaturatedUnsaturatedFattyAcidPolarheadgroupcaveolae胆固醇代谢异常与疾病CardiovasculardiseaseObesity

Gall-stoneAbnormalofcholesterolmetabolism脂肪肝-Fattyliver胆固醇代谢平衡CholesterolPool~100gAcetylCoA600-900mgDietaryCholesterol300-500mgBileAcids500-600mg600mgBiliaryCholesterolCholesterolPool~100gCholesterolPool~100gAcetylCoA600-900mgDietaryCholesterol300-500mgBileAcids500-600mg600mgBiliaryCholesterol胆固醇代谢平衡调控途径一.胆固醇合成途径(负反馈调控)二.胆固醇吸收途径三.胆固醇外排途径1.SREBPs转录水平调控2.胆固醇合成关键限速酶HMGCR蛋白降解调控1.低密度脂蛋白受体（LDLR）介导的胆固醇吸收2.NPC1L1介导的肝肠内游离胆固醇的吸收一.胆固醇合成途径WangX,BriggsMR,HuaX,YokoyamaC,GoldsteinJL,BrownMS.Nuclearproteinthatbindssterolregulatoryelementoflowdensitylipoproteinreceptorpromoter.II.Purificationandcharacterization.JBiolChem.1993Jul5;268(19):14497-504.YokoyamaC,WangX,BriggsMR,AdmonA,WuJ,HuaX,GoldsteinJL,BrownMS.SREBP-1,abasic-helix-loop-helix-leucinezipperproteinthatcontrolstranscriptionofthelowdensitylipoproteinreceptorgene.Cell.1993Oct8;75(1):187-97.WangX,SatoR,BrownMS,HuaX,GoldsteinJL.SREBP-1,amembrane-boundtranscriptionfactorreleasedbysterol-regulatedproteolysis.Cell.1994Apr8;77(1):53-62.胆固醇合成负反馈调控:SREBPs-膜结合的转录因子SREBPs调控的目的基因(HMGCR)胆固醇合成途径限速酶－HMGCRHMGCRLanosterol是调节HMGCR的内源分子SongBLetal,CellMetab,2005HMGCR通过泛素蛋白酶体途径降解SeverN*,SongBL*,YabeD*etal.,JBC,2003SongandDebose-boyd,JBC,2004ACNoAddition+SterolB泛素蛋白酶体途径甾醇调控HMGCR降解的分子机制Cao,J.,Wang,J.,etal.,CellMetab,2007二.胆固醇吸收途径细胞内胆固醇的动态运输平衡FrederickR.MaxfieldandIraTabas,Nature,2005家族性高胆固醇血症（低密度脂蛋白受体突变）(FamilialHypercholesterolemia,FH)杂合子患者血清总胆固醇较正常人高出1～2倍纯合子患者血清总胆固醇较正常人高出6～8倍杂合子患者发生率为1/500纯合子患者发生率为1/1,000,000杂合子患者男性30～40岁时，患CAD，23%患者在50岁以前死于CAD，>50%患者在60岁时明显的CAD症状；纯合子患者十几岁时，有严重的心血管事件甚至死亡LDLR突变----黄色瘤FH患者LDLR突变----眼底脂质渗出正常人LDL来源胆固醇在溶酶体中的运输HyockJooKwon,etal.,Cell,2009JoannaP.Davies,JBC,2000NPC1的拓扑结构EugeneD.Carstea,etal,Science,1997NPC疾病的细胞学表型NPC疾病

(Niemann-PickDiseaseTypeC)临床表型NPCisoneofseveralinheriteddiseasesofcholesterolmetabolism.Symptom:1)Enlargedliverandspleen2)Progressivelossofmotorskills,learningproblems,feedingdifficulties,dementia,andseizures3)ProgressivecentralnervoussystemdegenerationThemajority(~95%)ofthepatientshavebeenclassifiedasnpc1.NPC1L1在胆固醇吸收过程中发挥重要作用ScottW.Altmann,etal,Science,2004ABCXieetal.,JLR,2012NPC1L1介导的胆固醇在小肠中的吸收过程NPC1L1的拓扑结构Wang,J.,Chu,B.B.,et,al.,JLR,2009NPC1L1在细胞内循环转运与介导胆固醇吸收的分子机制WangandSong,2012,BBAXieetal.,2012,JLRGeetal.,2011,PNASXieetal.,201