膽固醇代謝平衡調控課件

膽固醇代謝平衡調控膽固醇代謝平衡調控1膽固醇的化學結構式Nobellaureates:1928Windans闡明膽固醇的結構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節(jié)機制膽固醇的化學結構式Nobellaureates:2膽固醇的生物學功能PhospholipidModifiedfromMolecularBiologyoftheCell,1994SaturatedUnsaturatedFattyAcidPolarheadgroup膽固醇的生物學功能PhospholipidModified3caveolaecaveolae4膽固醇代謝異常與疾病CardiovasculardiseaseObesity

Gall-stoneAbnormalofcholesterolmetabolism膽固醇代謝異常與疾病Cardiovasculardisea5脂肪肝-Fattyliver脂肪肝-Fattyliver6膽固醇代謝平衡CholesterolPool~100gAcetylCoA600-900mgDietaryCholesterol300-500mgBileAcids500-600mg600mgBiliaryCholesterolCholesterolPool~100gCholesterolPool~100gAcetylCoA600-900mgDietaryCholesterol300-500mgBileAcids500-600mg600mgBiliaryCholesterol膽固醇代謝平衡CholesterolPool~100gA7膽固醇代謝平衡調控途徑一.膽固醇合成途徑(負反饋調控)二.膽固醇吸收途徑三.膽固醇外排途徑1.SREBPs轉錄水平調控2.膽固醇合成關鍵限速酶HMGCR蛋白降解調控1.低密度脂蛋白受體（LDLR）介導的膽固醇吸收2.NPC1L1介導的肝腸內(nèi)游離膽固醇的吸收膽固醇代謝平衡調控途徑一.膽固醇合成途徑二.膽固醇吸收途徑三8一.膽固醇合成途徑一.膽固醇合成途徑9WangX,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.膽固醇合成負反饋調控:SREBPs-膜結合的轉錄因子WangX,BriggsMR,HuaX,Yoko10SREBPs調控的目的基因SREBPs調控的目的基因11膽固醇代謝平衡調控課件12(HMGCR)膽固醇合成途徑限速酶－HMGCRHMGCR(HMGCR)膽固醇合成途徑限速酶－HMGCRHMGCR13Lanosterol是調節(jié)HMGCR的內(nèi)源分子SongBLetal,CellMetab,2005Lanosterol是調節(jié)HMGCR的內(nèi)源分子SongBL14HMGCR通過泛素蛋白酶體途徑降解SeverN*,SongBL*,YabeD*etal.,JBC,2003SongandDebose-boyd,JBC,2004ACNoAddition+SterolBHMGCR通過泛素蛋白酶體途徑降解SeverN*,Son15泛素蛋白酶體途徑泛素蛋白酶體途徑16甾醇調控HMGCR降解的分子機制Cao,J.,Wang,J.,etal.,CellMetab,2007甾醇調控HMGCR降解的分子機制Cao,J.,Wang,17二.膽固醇吸收途徑二.膽固醇吸收途徑18膽固醇代謝平衡調控課件19細胞內(nèi)膽固醇的動態(tài)運輸平衡FrederickR.MaxfieldandIraTabas,Nature,2005細胞內(nèi)膽固醇的動態(tài)運輸平衡FrederickR.Maxf20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，患CAD，23%患者在50歲以前死于CAD，>50%患者在60歲時明顯的CAD癥狀；純合子患者十幾歲時，有嚴重的心血管事件甚至死亡家族性高膽固醇血癥（低密度脂蛋白受體突變）雜合子患者血清總膽21LDLR突變----黃色瘤LDLR突變----黃色瘤22FH患者LDLR突變----眼底脂質滲出正常人FH患者LDLR突變----眼底脂質滲出正常人23LDL來源膽固醇在溶酶體中的運輸HyockJooKwon,etal.,Cell,2009LDL來源膽固醇在溶酶體中的運輸HyockJooKwon24JoannaP.Davies,JBC,2000NPC1的拓撲結構JoannaP.Davies,JBC,2000NPC25EugeneD.Carstea,etal,Science,1997NPC疾病的細胞學表型EugeneD.Carstea,etal,Scie26NPC疾病

(Niemann-PickDiseaseTypeC)臨床表型NPCisoneofseveralinheriteddiseasesofcholesterolmetabolism.Symptom:1)Enlargedliverandspleen2)Progressivelossofmotorskills,learningproblems,feedingdifficulties,dementia,andseizures3)ProgressivecentralnervoussystemdegenerationThemajority(~95%)ofthepatientshavebeenclassifiedasnpc1.NPC疾病(Niemann-PickDiseaseTy27NPC1L1在膽固醇吸收過程中發(fā)揮重要作用ScottW.Altmann,etal,Science,2004ABCXieetal.,JLR,2012NPC1L1在膽固醇吸收過程中發(fā)揮重要作用ScottW.28NPC1L1介導的膽固醇在小腸中的吸收過程NPC1L1介導的膽固醇在小腸中的吸收過程29NPC1L1的拓撲結構Wang,J.,Chu,B.B.,et,al.,JLR,2009NPC1L1的拓撲結構Wang,J.,Chu,B.B.30NPC1L1在細胞內(nèi)循環(huán)轉運與介導膽固醇吸收的分子機制WangandSong,2012,BBAXieetal.,2012,JLRGeetal.,2011,PNASXieetal.,2011,JBCZhangetal.,2011,JBCChuetal.,2009,JBCWangetal.,2009,JLRGeetal.,2008,CellMetabolismNPC1L1在細胞內(nèi)循環(huán)轉運與介導膽固醇吸收的分子機制Wan31謝謝！謝謝！32膽固醇代謝平衡調控膽固醇代謝平衡調控33膽固醇的化學結構式Nobellaureates:1928Windans闡明膽固醇的結構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節(jié)機制膽固醇的化學結構式Nobellaureates:34膽固醇的生物學功能PhospholipidModifiedfromMolecularBiologyoftheCell,1994SaturatedUnsaturatedFattyAcidPolarheadgroup膽固醇的生物學功能PhospholipidModified35caveolaecaveolae36膽固醇代謝異常與疾病CardiovasculardiseaseObesity

Gall-stoneAbnormalofcholesterolmetabolism膽固醇代謝異常與疾病Cardiovasculardisea37脂肪肝-Fattyliver脂肪肝-Fattyliver38膽固醇代謝平衡CholesterolPool~100gAcetylCoA600-900mgDietaryCholesterol300-500mgBileAcids500-600mg600mgBiliaryCholesterolCholesterolPool~100gCholesterolPool~100gAcetylCoA600-900mgDietaryCholesterol300-500mgBileAcids500-600mg600mgBiliaryCholesterol膽固醇代謝平衡CholesterolPool~100gA39膽固醇代謝平衡調控途徑一.膽固醇合成途徑(負反饋調控)二.膽固醇吸收途徑三.膽固醇外排途徑1.SREBPs轉錄水平調控2.膽固醇合成關鍵限速酶HMGCR蛋白降解調控1.低密度脂蛋白受體（LDLR）介導的膽固醇吸收2.NPC1L1介導的肝腸內(nèi)游離膽固醇的吸收膽固醇代謝平衡調控途徑一.膽固醇合成途徑二.膽固醇吸收途徑三40一.膽固醇合成途徑一.膽固醇合成途徑41WangX,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.膽固醇合成負反饋調控:SREBPs-膜結合的轉錄因子WangX,BriggsMR,HuaX,Yoko42SREBPs調控的目的基因SREBPs調控的目的基因43膽固醇代謝平衡調控課件44(HMGCR)膽固醇合成途徑限速酶－HMGCRHMGCR(HMGCR)膽固醇合成途徑限速酶－HMGCRHMGCR45Lanosterol是調節(jié)HMGCR的內(nèi)源分子SongBLetal,CellMetab,2005Lanosterol是調節(jié)HMGCR的內(nèi)源分子SongBL46HMGCR通過泛素蛋白酶體途徑降解SeverN*,SongBL*,YabeD*etal.,JBC,2003SongandDebose-boyd,JBC,2004ACNoAddition+SterolBHMGCR通過泛素蛋白酶體途徑降解SeverN*,Son47泛素蛋白酶體途徑泛素蛋白酶體途徑48甾醇調控HMGCR降解的分子機制Cao,J.,Wang,J.,etal.,CellMetab,2007甾醇調控HMGCR降解的分子機制Cao,J.,Wang,49二.膽固醇吸收途徑二.膽固醇吸收途徑50膽固醇代謝平衡調控課件51細胞內(nèi)膽固醇的動態(tài)運輸平衡FrederickR.MaxfieldandIraTabas,Nature,2005細胞內(nèi)膽固醇的動態(tài)運輸平衡FrederickR.Maxf52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，患CAD，23%患者在50歲以前死于CAD，>50%患者在60歲時明顯的CAD癥狀；純合子患者十幾歲時，有嚴重的心血管事件甚至死亡家族性高膽固醇血癥（低密度脂蛋白受體突變）雜合子患者血清總膽53LDLR突變----黃色瘤LDLR突變----黃色瘤54FH患者LDLR突變----眼底脂質滲出正常人FH患者LDLR突變----眼底脂質滲出正常人55LDL來源膽固醇在溶酶體中的運輸HyockJooKwon,etal.,Cell,2009LDL來源膽固醇在溶酶體中的運輸HyockJooKwon56JoannaP.Davies,JBC,2000NPC1的拓撲結構JoannaP.Davies,JBC,2000NPC57EugeneD.Carstea,etal,Science,1997NPC疾病的細胞學表型EugeneD.Carstea,etal,Scie58NPC疾病

(Niemann-PickDiseaseTypeC)臨床表型NPCisoneofseveralinheriteddiseasesofcholesterolmetabolism.Symptom:1)Enlargedliverandspleen2)Progressivelossofmotorskills,learningprobl