膽固醇代謝平衡調(diào)控

膽固醇代謝平衡調(diào)控膽固醇的化學(xué)結(jié)構(gòu)式Nobellaureates:1928Windans闡明膽固醇的結(jié)構(gòu)1964Bloch&Lynen闡明膽固醇從頭合成途徑1985MichaelS.Brown&JosephL.Goldstein發(fā)現(xiàn)低密度脂蛋白受體，闡明膽固醇代謝的調(diào)節(jié)機(jī)制膽固醇的生物學(xué)功能PhospholipidModifiedfromMolecularBiologyoftheCell,1994SaturatedUnsaturatedFattyAcidPolarheadgroupcaveolae膽固醇代謝異常與疾病CardiovasculardiseaseObesityGall-stoneAbnormalofcholesterolmetabolism脂肪肝-Fattyliver膽固醇代謝平衡CholesterolPool~100gAcetylCoA600-900mgDietaryCholesterol300-500mgBileAcids500-600mg600mgBiliaryCholesterolCholesterolPool~100gCholesterolPool~100gAcetylCoA600-900mgDietaryCholesterol300-500mgBileAcids500-600mg600mgBiliaryCholesterol膽固醇代謝平衡調(diào)控途徑一.膽固醇合成途徑(負(fù)反饋調(diào)控)二.膽固醇吸收途徑三.膽固醇外排途徑1.SREBPs轉(zhuǎn)錄水平調(diào)控2.膽固醇合成關(guān)鍵限速酶HMGCR蛋白降解調(diào)控1.低密度脂蛋白受體（LDLR）介導(dǎo)的膽固醇吸收2.NPC1L1介導(dǎo)的肝腸內(nèi)游離膽固醇的吸收一.膽固醇合成途徑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.膽固醇合成負(fù)反饋調(diào)控:SREBPs-膜結(jié)合的轉(zhuǎn)錄因子SREBPs調(diào)控的目的基因(HMGCR)膽固醇合成途徑限速酶－HMGCRHMGCRLanosterol是調(diào)節(jié)HMGCR的內(nèi)源分子SongBLetal,CellMetab,2005HMGCR通過泛素蛋白酶體途徑降解SeverN*,SongBL*,YabeD*etal.,JBC,2003SongandDebose-boyd,JBC,2004ACNoAddition+SterolB泛素蛋白酶體途徑甾醇調(diào)控HMGCR降解的分子機(jī)制Cao,J.,Wang,J.,etal.,CellMetab,2007二.膽固醇吸收途徑細(xì)胞內(nèi)膽固醇的動(dòng)態(tài)運(yùn)輸平衡FrederickR.MaxfieldandIraTabas,Nature,2005家族性高膽固醇血癥（低密度脂蛋白受體突變）(FamilialHypercholesterolemia,FH)雜合子患者血清總膽固醇較正常人高出1～2倍純合子患者血清總膽固醇較正常人高出6～8倍雜合子患者發(fā)生率為1/500純合子患者發(fā)生率為1/1,000,000雜合子患者男性30～40歲時(shí)，患CAD，23%患者在50歲以前死于CAD，>50%患者在60歲時(shí)明顯的CAD癥狀；純合子患者十幾歲時(shí)，有嚴(yán)重的心血管事件甚至死亡LDLR突變----黃色瘤FH患者LDLR突變----眼底脂質(zhì)滲出正常人LDL來源膽固醇在溶酶體中的運(yùn)輸HyockJooKwon,etal.,Cell,2009JoannaP.Davies,JBC,2000NPC1的拓?fù)浣Y(jié)構(gòu)EugeneD.Carstea,etal,Science,1997NPC疾病的細(xì)胞學(xué)表型NPC疾病

(Niemann-PickDiseaseTypeC)臨床表型NPCisoneofseveralinheriteddiseasesofcholesterolmetabolism.Symptom:1)Enlargedliverandspleen2)Progressivelossofmotorskills,learningproblems,feedingdifficulties,dementia,andseizures3)ProgressivecentralnervoussystemdegenerationThemajority(~95%)ofthepatientshavebeenclassifiedasnpc1.NPC1L1在膽固醇吸收過程中發(fā)揮重要作用ScottW.Altmann,etal,Science,2004ABCXieetal.,JLR,2012NPC1L1介導(dǎo)的膽固醇在小腸中的吸收過程N(yùn)PC1L1的拓?fù)浣Y(jié)構(gòu)Wang,J.,Chu,B.B.,et,al.,JLR,2009NPC1L1在細(xì)胞內(nèi)循環(huán)轉(zhuǎn)運(yùn)與介導(dǎo)膽固醇吸收的分子機(jī)制WangandSong,2012,BBAXieetal.,