E4orf1 Improves Lipid and Glucose Metabolism in Hepatocytes A Template to Improve Steatosis Hyperglycemia 英文参考文献.docVIP

E4orf1ImprovesLipidandGlucoseMetabolismin Hepatocytes:ATemplatetoImproveSteatosis Hyperglycemia EmilyJ.Dhurandhar1,RashmiKrishnapuram1,VijayHegde1,OlgaDubuisson1,RongyaTao2 ,X. CharlieDong2,JianpingYe1,NikhilV.Dhurandhar1* 1Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, United States of America, 2Department of Biochemistry and MolecularBiology,IndianaUniversitySchoolofMedicine,Indianapolis,Indiana,UnitedStatesofAmerica Abstract Hepatic steatosis often accompanies obesity and insulin resistance. The cornerstones of steatosis treatment include reducingbodyweightanddietaryfatintake,whicharemarginallysuccessfuloverthelongterm.Ad36,ahumanadenovirus, may offer a template to overcome these limitations. In vitro and in vivo studies collectively indicate that via its E4orf1 protein,Ad36improveshyperglycemia,andattenuateshepaticsteatosis,despiteahighfatdietandwithoutweightloss. Consideringthathepaticinsulinsensitivity,orthesynthesis,oxidation,orexportoffattyacidbyhepatocytesarethekey determinantofhepaticlipidstorage,wedeterminedtheroleofE4orf1proteininmodulatingthesephysiologicalpathways. Forthisstudy,HepG2cells,ormouseprimaryhepatocytesweretransfectedwithE4orf1orthenullvector.Glucoseoutput byhepatocyteswasdeterminedundergluconeogenicconditions(cAMPanddexamethasone,orglucagonexposure).Also, de-novo lipogenesis, palmitate oxidation, and lipid export as determined by apoB secretion were measured 48h post transfection. Results show that compared to null vector transfected cells, E4orf1 significantly reduced glucose output in basal and gluconeogenic conditions. E4orf1 reduced de-novo lipogenesis by about 35%, increased complete fatty acid oxidation 2-fold (p,0.0001), and apoB secretion 1.5 fold(p,0.003). Response of key signaling molecules to E4orf1 transfectionwasinagreementwiththesefindings.Thus,E4orf1offersavaluabletemplatetoexogenouslymodulatehepatic glucoseandlipidmetabolism.Elucidatingtheunderlyingmolecularmechanismmayhel