胆固醇代谢平衡调控.pptx

胆固醇代谢平衡调控胆固醇代谢平衡调控胆固醇的化学结构式胆固醇的化学结构式Nobel laureates:1928 Windans 阐明胆固醇的结构阐明胆固醇的结构1964 Bloch&Lynen 阐明胆固醇从头合成途径阐明胆固醇从头合成途径1985 Michael S.Brown&Joseph L.Goldstein发现低密度脂蛋白受体，阐明胆固醇代谢的调节机制发现低密度脂蛋白受体，阐明胆固醇代谢的调节机制胆固醇的生物学功能胆固醇的生物学功能PhospholipidModified fromMolecular Biology of the Cell,1994SaturatedUnsaturatedFatty AcidPolar head groupcaveolae胆固醇代谢异常与疾病胆固醇代谢异常与疾病Cardiovascular diseaseObesity Gall-stoneAbnormal of cholesterol metabolism脂肪肝脂肪肝-Fatty liver胆固醇代谢平衡胆固醇代谢平衡Cholesterol Pool100 gAcetyl CoA600-900 mgDietary Cholesterol300-500 mgBile Acids500-600 mg600 mgBiliaryCholesterolCholesterol Pool100 gCholesterol Pool100 gAcetyl CoA600-900 mgDietary Cholesterol300-500 mgBile Acids500-600 mg600 mgBiliaryCholesterol胆固醇代谢平衡调控途径胆固醇代谢平衡调控途径一一.胆固醇合成途径胆固醇合成途径(负反馈调控负反馈调控)二二.胆固醇吸收途径胆固醇吸收途径三三.胆固醇外排途径胆固醇外排途径1.SREBPs转录水平调控转录水平调控2.胆固醇合成关键限速酶胆固醇合成关键限速酶HMGCR蛋白降解调控蛋白降解调控1.低密度脂蛋白受体（低密度脂蛋白受体（LDLR）介导的胆固醇吸收介导的胆固醇吸收2.NPC1L1介导的肝肠内游离胆固醇的吸收介导的肝肠内游离胆固醇的吸收一一.胆固醇合成途径胆固醇合成途径Wang X,Briggs MR,Hua X,Yokoyama C,Goldstein JL,Brown MS.Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter.II.Purification and characterization.J Biol Chem.1993 Jul 5;268(19):14497-504.Yokoyama C,Wang X,Briggs MR,Admon A,Wu J,Hua X,Goldstein JL,Brown MS.SREBP-1,a basic-helix-loop-helix-leucine zipper protein that controls transcription of the low density lipoprotein receptor gene.Cell.1993 Oct 8;75(1):187-97.Wang X,Sato R,Brown MS,Hua X,Goldstein JL.SREBP-1,a membrane-bound transcription factor released by sterol-regulated proteolysis.Cell.1994 Apr 8;77(1):53-62.胆固醇合成负反馈调控胆固醇合成负反馈调控:SREBPs-膜结合的转录因子膜结合的转录因子SREBPs调控的目的基因调控的目的基因(HMGCR)胆固醇合成途径限速酶胆固醇合成途径限速酶HMGCRHMGCRLanosterol是调节是调节HMGCR的内源分子的内源分子Song BL et al,Cell Metab,2005HMGCR通过泛素蛋白酶体途径降解通过泛素蛋白酶体途径降解Sever N*,Song BL*,Yabe D*et al.,JBC,2003 Song and Debose-boyd,JBC,2004ACNo Addition+SterolB泛素蛋白酶体途径泛素蛋白酶体途径甾醇调控甾醇调控HMGCR降解的分子机制降解的分子机制Cao,J.,Wang,J.,et al.,Cell Metab,2007二二.胆固醇吸收途径胆固醇吸收途径细胞内胆固醇的动态运输平衡细胞内胆固醇的动态运输平衡Frederick R.Maxfield and Ira Tabas,Nature,2005家族性高胆固醇血症（低密度脂蛋白受体突变）家族性高胆固醇血症（低密度脂蛋白受体突变）(Familial Hypercholesterolemia,FH)杂合子患者血清总胆固醇较正常人高出杂合子患者血清总胆固醇较正常人高出1 12 2倍倍纯合子患者血清总胆固醇较正常人高出纯合子患者血清总胆固醇较正常人高出6 68 8倍倍杂合子患者发生率为杂合子患者发生率为1/5001/500纯合子患者发生率为纯合子患者发生率为1/1,000,0001/1,000,000杂合子患者男性杂合子患者男性30304040岁时，患岁时，患CADCAD，23%23%患者在患者在5050岁以前岁以前死于死于CADCAD，50%50%患者在患者在6060岁时明显的岁时明显的CADCAD症状；症状；纯合子患者十几岁时，有严重的心血管事件甚至死亡纯合子患者十几岁时，有严重的心血管事件甚至死亡LDLR突变突变-黄色瘤黄色瘤FHFH患者患者患者患者LDLR突变突变-眼底脂质渗出眼底脂质渗出正常人正常人正常人正常人LDL来源胆固醇在溶酶体中的运输来源胆固醇在溶酶体中的运输Hyock Joo Kwon,et al.,Cell,2009Joanna P.Davies,JBC,2000NPC1的拓扑结构的拓扑结构Eugene D.Carstea,et al,Science,1997 NPC疾病的细胞学表型疾病的细胞学表型NPC疾病疾病(Niemann-Pick Disease Type C)临床表型临床表型NPC is one of several inherited diseases of cholesterol metabolism.Symptom:1)Enlarged liver and spleen 2)Progressive loss of motor skills,learning problems,feeding difficulties,dementia,and seizures 3)Progressive central nervous system degenerationThe majority(95%)of the patients have been classified as npc1.NPC1L1在胆固醇吸收过程中发挥重要作用在胆固醇吸收过程中发挥重要作用Scott W.Altmann,et al,Science,2004 ABCXie et al.,JLR,2012 NPC1L1介导的胆固醇在介导的胆固醇在小肠中的小肠中的吸收过程吸收过程NPC1L1的拓扑结构的拓扑结构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在细胞内循环转运与介导胆固醇吸收的分子机制Wang and Song,2012,BBAXie et al.,2012,JLRGe et al.,2011,PNASXie et al.,2011,JBCZhang et al.,2011,JBCChu et al.,2009,JBCWang et al.,2009,JLRGe et al.,2008,Cell Metabolism谢谢 谢！谢！