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1、Chapter30Cholesterolmetabolism,Outline,BiosynthesisofCholesterolTransportofCholesterolConversionofCholesterolRegulationofCholesterolMetabolism,Topfourreasonsweneedcholesterol,Membranecomponent-controlsfluidityPrecursorofbileacidsandbilesaltsPrecursorofsteroidhormonesPrecursorofvitaminD,Sterolsgalore
2、!,Structureofcholesterol,Siteofattachmentoffattyacidincholesterolester,Cholesterolbiosynthesis,Precursorforcholesterolbiosynthesis-acetylCoAAlsorequiresNADPHandATPFour-stagereaction:Acetate(C2)Isoprenoid(C5)Squalene(30)Cholesterol(27)HighlyregulatedprocessOccursinthecytoplasmEndoplasmicreticulumCyto
3、sol,Fourstagesofcholesterolsynthesis,AcetylCoAtoIsopentenylDiphosphate,Synthesisofmevalonate,Conversiontoactivatedisoprenes,HMG-CoAreductase,IntegralmembraneproteinintheERCarriesoutanirreversiblereactionIsanimportantregulatoryenzymeincholesterolsynthesis,Condensationofisoprenes,Headtotail,Isoprenoid
4、sgalore!,Furthercondensationofisoprenes,Andevenmorecondensationofisoprenes,Fromsqualenetocholesterol,Cholesteroltrafficking/delivery,Plasmalipoproteinscarrycholesterolandotherlipids(triacylglycerols)throughoutthebody,Plasmalipoproteins,=lipids+ApolipoproteinsChylomicrons-CM(Intestine)VeryLowDensityL
5、ipoprotein-VLDL(Liver)IDL(intermediatedensitylipoprotein)LowDensityLipoprotein-LDLHighDensityLipoprotein-HDLVLDLIDLLDL,Apolipoproteins,“apo”=lipid-freeformoftheproteinspecificlipid/cholesterolcarrierproteinsthatallowdistributionofcholesterolandvariouslipidsthroughbloodsysteminteractwithspecificrecep
6、torsand/ormodulateenzymeactivity9differentapolipoproteinsinhumans,Apolipoproteinfunctions,Fourtypesoflipoproteinsundermicroscope,Low-densitylipoprotein(LDL),DerivedfromVLDLsuponlossoftriacylglycerolsveryrichincholesterol&cholesterylesterstransportofcholesterolandtheiresterstoextrahepatictissuesapoB-
7、100receptormediateduptakeassociatedapolipoproteins-predominantlyapoB-100,:(,LDL:theinfamouslipoprotein,Receptor-mediatedLDLendocytosis,apoB-100bindstoLDLreceptorreceptorbindingtriggersendocytosisandformationofendosomeendosomefuseswithlysosomedigestionofLDLliposomeandrelocationofreceptortothesurface,
8、TheroleofLDLandHDLincholesterolmetabolism,High-densitylipoprotein(HDL),synthesisofHDLbeginsintheliverandsmallintestinecontainstheenzymelecithin-cholesterolacyltransferase(LCAT)=formationofcholesterylestersfromlecithin+cholesterolreturnstotheliverwhereitunloadsthecholesterol,someofwhichisthenturnedin
9、tobilesaltstakenupintheliverviareceptormediatedendocytosisalsobindstoSR-BIreceptorsinhepatictissuesandadrenalgland=partialtransferofcholesterol,:),HMG-CoAReductase,therate-limitingsteponthepathwayforsynthesisofcholesterol,isamajorcontrolpoint.Short-termregulation:-HMG-CoAReductaseisinhibitedbyphosph
10、orylation,catalyzedbyAMP-activatedProteinKinase.-ThiskinaseisactivewhencellularAMPishigh,correspondingtowhenATPislow.WhenAMPishigh,whywasteenergyoncholesterolsynthesis?Long-termregulationisbyvariedtranscriptionanddegradationofHMG-CoAReductaseandotherenzymesofthepathwayforsynthesisofcholesterol.,Regu
11、lationofCholesterolSynthesis,Regulationofcholesterolmetabolismbothuptakeandsynthesisareinvolved,RegulatedproteolysisofHMG-CoAReductase:DegradationofHMG-CoAReductaseisstimulatedbycholesterol,oxidizedderivativesofcholesterol,mevalonate,&farnesol(dephosphorylatedfarnesylpyrophosphate).HMG-CoAReductasei
12、ncludesatransmembranesterol-sensingdomainthathasaroleinactivatingdegradationoftheenzymeviatheproteasome(proteasometobediscussedlater).,Long-termregulationII,Regulatedtranscription:AtranscriptionfactorSREBP-2(sterolregulatoryelementbindingprotein#2)respondstocellularlevelsofsterols.(TherelatedSREBP-1
13、hasaroleinregulatingfattyacidsynthesis.)Whensterollevelsarelow,SREBP-2isreleasedbycleavageofaprecursorproteinfoundinendoplasmicreticulummembranes.AcytosolicdomaincleavedfromtheSREBPprecursorproteinthentranslocatesintothenucleuswhereitfunctionsasatranscriptionfactortoactivatetranscriptionofgenesforHM
14、G-CoAReductaseandotherenzymesofthepathwayforcholesterolsynthesis.,ThreeotherproteinsareinvolvedintheactivationofSREBP-2inresponsetosterollevels,SCAP(SREBPcleavage-activatingprotein)-AnintegralproteinofERmembranesthathasatransmembranesterol-sensingdomainhomologoustothatofHMG-CoAReductase.-SCAPisinhib
15、itedbybindingofsterols.-Whensterollevelsarelow,SCAPbindsandtransportstheSREBPprecursorproteinfromtheendoplasmicreticulumtothegolgiapparatus.ProteaseS1P(siteoneprotease),anintegralproteinofgolgimembranes,cleavestheSREBPprecursorataparticularsiteinthelumenaldomain.ProteaseS2Pthencleaveswithinatrans-me
16、mbranesegmentoftheSREBPprecursor,releasingtothecytosoltheN-terminalSREBPdomainthatfunctionsasatranscriptionfactor.,SREBPcleavageactivatingprotein,Site1andsite2protease-,Degradationofcholesterol,RingstructurenotmetabolizedCholesteroleliminatedbytwomeans:Conversiontobileacids(excretedinfeces)Secretion
17、intobile(transporttointestine),Cholesterolandheartdisease,Heartdiseaseisthe#1killerintheUSAExcesscholesterol(LDL)inthebloodresultsinatherosclerosis,(cloggingofbloodvessels)Inheritablehypercholesterolemiacausessevereatherosclerosisinchildhood(LDLishigh,HDLislow)Therapy:HMG-CoAreductaseistheregulatoryenzymeinthecholesterolsynthesispathwayLovastatinandcompactininhibitHMG-CoAreductase,