胆固醇代谢

胆固醇代谢平衡调控提纲1.胆固醇的生物学功能2.胆固醇相关疾病3.胆固醇的生物合成4.胆固醇在血液中的运输5.家族型高胆固醇血症6.NPC疾病7.胆固醇的降解与清除8.胆固醇代谢的负反馈调控机制—SCAP-SREBP途径9.胆固醇代谢的负反馈调控机制—HMGCR降解途径10.饮食胆固醇吸收的分子途径Cholesterol（胆固醇）一、胆固醇的生物学功能MembraneFluidityBileAcidsHormones、VitaminDSynapseHedgehogModificationSignalTransduction……哺乳动物细胞模式图膜上的微结构域Cholesterolandcholesterolderivatives雌激素雄激素脂肪酸、糖等提供能量（ATP）胆固醇并不提供能量二、胆固醇相关疾病Cholesterolisthemajorcauseofatherosclerosis心脑血管疾病恶性肿瘤肺炎、流感感染性疾病意外死亡慢性阻塞性肺病肝病及肝硬化糖尿病肾病其它43.8%22.3%FromHeJ.etal.,NEnglJMed,(2005),353:1124-1134.中国死亡原因统计蒙娜丽莎患有高胆固醇？意大利帕勒莫大学的病理解剖学教授弗兰克，研究认为蒙娜丽莎饮食不健康，患有高胆固醇症。正是眼部的脂肪瘤，造成了蒙娜丽莎这副神秘莫测的表情。画中的她（或者说达芬奇的这个模特）正在为自己体内过高的胆固醇而担忧。胆结石老年痴呆症CholesterolandDiseasesNiemann-PickTypeCDisease糖尿病/肥胖症FromIMSHealth,MIDAS药品销售排行榜NameCompanyIndicationSalestoJune07($bn)LipitorPfizerHypercholesterolaemia（高胆固醇血症）13.5NexiumAstraZenecaGastroesophagealreflux（胃食管返流）,gastriculcers（胃溃疡）6.9SeretideGSKAsthma（哮喘）6.7PlavixBristol-MyersSquibbAtheroscleroticevents（动脉粥样硬化症）5.8AranespAmgenAnaemia（贫血症）5.1三、胆固醇的生物合成Cholesterolisnotrequiredinthediet•CholesterolisanessentialmoleculebutisnotrequiredinthedietbecauseallcellscansynthesizeitfromsimpleprecursorsCholesterolismadefromacetyl-CoAinfourstages•allofitscarbonatomsareprovidedbyasingleprecursor–acetateStage1•Threeacetateunitscondensetoformasixcarbonintermediate,mevalonate•Twomoleculesofacetate-CoAcondenseformingacetoacetyl-CoA.•Acetoacetyl-CoAcondenseswithacetyl-CoAtoyieldb-hydroxy-b-methylglutaryl-CoA(HMG-CoA)•ThefinalstepthereductionofHMG-CoAtomevalonate,catalyzedbyHMG-CoAreductase.Stage2•Conversionofmevalonateintoactivatedisopreneunits•IsoprenecontainingmoleculesareimportantintermediatesincholesterolbiosynthesisStage3•Polymerizationofsix5-carbonisopreneunitstoformthe30-carbonlinearstructureofsqualene.•Cyclizationofsqualeneformsthefourringsofthesteroidnucleus.Subsequentmodificationsleadstothefinalproduct,cholesterol.Stage4Mostofthecholesterolmadeintheliverisexported•Muchofcholesterolsynthesistakesplaceintheliver•MostisexportedCholesterolisexportedinthreeforms1.Bilesalts–amphipathiccholesterolderivativesthataidlipiddigestion2.Cholesterol–tobile3.Cholesterylesters–transportedandsecretedinlipoproteinparticlestoothertissuesthatusecholesterolorarestoredintheliver四、胆固醇在血液中的运输CholesterylesterformationFormedintheliverConvertingcholesteroltoamorehydrophobicformCholesteroltransport:theproblem•Cholesterolandcholesterylestersareessentiallyinsolubleinwater•ThesemoleculesmustbemovedfromthetissueoforigintothetissuesinwhichtheyarestoredorareconsumedCholesteroltransport:thesolution•CholesterolandcholesterylestersarecarriedinthebloodplasmafromonetissuetoanotherasplasmalipoproteinsCholesterolestersentercellsbyreceptormediatedendocytosis五、家族型高胆固醇血症LDLreceptor(LDLR)突变家族性高胆固醇血症(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六、Niemann-PicktypeC(NPC)疾病溶酶体堆积型疾病（LysosomalStorageDisorders）胆固醇在溶酶体中堆积进行性神经细胞死亡、肝脾肿大、小脑共济失调、痴呆、语言吞咽困难、青春期之前死亡1：120，000发病，携带者1：100NPC1（大的膜蛋白）或NPC2（小的可溶蛋白）基因突变临床尝试用环化糊精进行治疗正常细胞NPC1突变细胞七、胆固醇的降解与清除Degradationofcholesterol•TheringstructureofcholesterolcannotbemetabolizedtoCO2andH2Oinhumans•Theintactsterolringiseliminatedfromthebodyby:1.Conversiontobileacids,whichareexcretedinfeces2.Secretionofcholesterolintothebile,whichtransportsittotheintestineforeliminationSteroidhormonesareformedfromcholesterol•Allsteroidhormonesarederivedformcholesterol•Inthecortexofadrenalglandstwoclassesofhormonesaresynthesized–mineralocorticoidsandglucocorticoids•Inthemaleandfemalegonads–sexhormonesareproduced•Sexhormonesinclude–progesterone,androgensandestrogens八、胆固醇代谢的负反馈调控机制（一）SCAP-SREBP途径脂质代谢的关键蛋白质及其功能调控的临床意义LDLReceptorsLDLHMGCRSREBPPathwayHMGCRinhibitorInsigSREBP—膜结合的转录因子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):53-62.25-Hydroxycholesterol-irradiationMutantcellssurvive(25-RA)AmphotericinB-irradiationCholesterolauxotrophs(M19)HumanfibroblasmgenomicDNAtoM19cellsHfT1M19(c)Growinlipid-deficientmediumGrowinlipid-deficientmediumHfT1M19(c)genomicDNAtoM19cellsHfT2M19(c)Growinlipid-deficientmediumHfT2M19(c)genomicDNAtoM19cellsHfT3M19(c)Inter-AluPCR,usethisprobetoscreengenomicPAClibrary,transfectPACcloneintoM19,sequencePACcloneandcomparewithEST.S2PcDNAtoCHOcellsBrieflyincubatedwithLDL,AmphotericinBselection-irradiationLowfluorescentLDLuptake-irradiationSRD-12BDeBose-BoydRA,BrownMS,LiWP,NohturfftA,GoldsteinJL,EspenshadePJ.Transport-dependentproteol