Maturation and Activity of Sterol Regulatory Element Binding Protein 1 Is Inhibited by Acyl-CoA Binding Domain Containing 3 英文参考文献.docVIP

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Maturation and Activity of Sterol Regulatory Element Binding Protein 1 Is Inhibited by Acyl-CoA Binding Domain Containing 3 英文参考文献.doc

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Maturation and Activity of Sterol Regulatory Element Binding Protein 1 Is Inhibited by Acyl-CoA Binding Domain Containing 3 英文参考文献

MaturationandActivityofSterolRegulatoryElement BindingProtein1IsInhibitedbyAcyl-CoABinding DomainContaining3 YongChen1,VishalaPatel2,SookheeBang1,NatalieCohen1,JohnMillar2,SangwonF.Kim1* 1DepartmentofPsychiatry,CenterforNeurobiologyandBehavior,UniversityofPennsylvania,Philadelphia,Pennsylvania,UnitedStatesofAmerica,2MetabolicTracer Resource,InstituteofDiabetes,ObesityMetabolism,UniversityofPennsylvania,Philadelphia,Pennsylvania,UnitedStatesofAmerica Abstract Imbalanceoflipidmetabolismhasbeenlinkedwithpathogenesisofavarietyofhumanpathologicalconditionssuchas diabetes, obesity, cancer and neurodegeneration. Sterol regulatory element binding proteins (SREBPs) are the master transcriptionfactorscontrollingthehomeostasisoffattyacidsandcholesterolinthebody.Transcription,expression,and activity of SREBPs are regulated by various nutritional, hormonal or stressful stimuli, yet the molecular and cellular mechanisms involved in these adaptative responses remains elusive. In the present study, we found that overexpressed acyl-CoA binding domain containing 3 (ACBD3), a Golgi-associated protein, dramatically inhibited SREBP1-sensitive promoteractivityoffattyacidsynthase(FASN).Moreover,lipiddeprivation-stimulatedSREBP1maturationwassignificantly attenuatedbyACBD3.Withcellfractionation,geneknockdownandimmunoprecipitationassays,itwasshowedthatACBD3 blockedintracellularmaturationofSREBP1probablythroughdirectlybindingwiththelipidregulatorratherthandisrupted SREBP1-SCAP-Insig1 interaction. Further investigation revealed that acyl-CoA domain-containing N-terminal sequence of ACBD3contributedtoitsinhibitoryeffectsontheproductionofnuclearSREBP1.Inaddition,mRNAandproteinlevelsof FASN and de novo palmitate biosynthesis were remarkably reduced in cells overexpressed with ACBD3. These findings suggestthatACBD3playsanessentialroleinmaintaininglipidhomeostasisviaregulatingSREBP1’sprocessingpathway andthusimpactingcellularlipogenesis. Citation:ChenY,PatelV,BangS,CohenN,MillarJ,etal.(2012)Matur