RLIP76, a Glutathione-Conjugate Transporter, Plays a Major Role in the Pathogenesis of Metabolic Syndrome 英文参考文献.docVIP

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RLIP76, a Glutathione-Conjugate Transporter, Plays a Major Role in the Pathogenesis of Metabolic Syndrome 英文参考文献.doc

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RLIP76, a Glutathione-Conjugate Transporter, Plays a Major Role in the Pathogenesis of Metabolic Syndrome 英文参考文献

RLIP76,aGlutathione-ConjugateTransporter,Playsa MajorRoleinthePathogenesisofMetabolicSyndrome JyotsanaSinghal1,LokeshNagaprashantha1,RitVatsyayan2,SanjayAwasthi1,SharadS.Singhal1* 1Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute, City of Hope, National Medical Center, Duarte, California, United States of America,2DepartmentofMolecularBiologyandImmunology,UniversityofNorthTexasHealthScienceCenter,FortWorth,Texas,UnitedStatesofAmerica Abstract Purpose: Characteristic hypoglycemia, hypotriglyceridemia, hypocholesterolemia, lower body mass, and fat as well as pronounced insulin-sensitivity of RLIP762/2 mice suggested to usthe possibility that elevation of RLIP76 in response to stresscoulditselfelicitmetabolicsyndrome(MSy).Indeed,ifitwererequiredforMSy,drugsusedtotreatMSyshouldhave noeffectonRLIP762/2 mice. ResearchDesignandMethods:Bloodglucose(BG)andlipidmeasurementswereperformedinRLIP76+/+andRLIP762/2 mice,usingAscensiaEliteGlucometerHforglucoseandIDLabskitsforcholesterolandtriglyceridesassays.Theultimate effectorsofgluconeogenesisarethethreeenzymes:PEPCK,F-1,6-BPase,andG6Pase,andtheirexpressionisregulatedby PPARcandAMPK.Theactivityoftheseenzymeswastestedbyprotocolsstandardizedbyus.ExpressionsofRLIP76,PPARa, PPARc,HMGCR,pJNK,pAkt,andAMPKwereperformedbyWestern-blotandtissuestaining. Results:TheconcomitantactivationofAMPKandPPARcbyinhibitingtransportactivityofRLIP76,despiteinhibitedactivity ofkeyglucocorticoid-regulated hepaticgluconeogenicenzymeslikePEPCK,G6PaseandF-1,6-BPin RLIP762/2 mice, isa salientfindingofourstudies.ThedecreaseinRLIP76proteinexpressionbyrosiglitazoneandmetforminisassociatedwith anup-regulationofPPARcandAMPK. Conclusions/Significance:Allfourdrugs,rosiglitazone,metformin,gemfibrozilandatorvastatinfailedtoaffectglucoseand lipidmetabolisminRLIP762/2mice.StudiesconfirmedamodelinwhichRLIP76playsacentralroleinthepathogenesisof MSyandRLIP76losscausesprofoundandglobalalterationsofMSysignalingfunctions.RLIP76isanovel