胆固醇代谢平衡调控.ppt

胆固醇代谢平衡调控,胆固醇的化学结构式,Nobellaureates:1928Windans阐明胆固醇的结构1964Bloch268(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,胆固醇合成途径限速酶HMGCR,HMGCR,Lanosterol是调节HMGCR的内源分子,SongBLetal,CellMetab,2005,HMGCR通过泛素蛋白酶体途径降解,SeverN*,SongBL*,YabeD*etal.,JBC,2003SongandDebose-boyd,JBC,2004,A,C,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12倍纯合子患者血清总胆固醇较正常人高出68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3040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,2009,JoannaP.Davies,JBC,2000,NPC1的拓扑结构,EugeneD.Carstea,etal,Science,1997,NPC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,2004,A,B,C,Xieetal.,JLR,2012,NPC1L1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,2009,NPC1L1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.,2011,J