HNF4alpha and HNF1alpha Dysfunction as a Molecular Rational for Cyclosporine Induced Posttransplantation Diabetes Mellitus 英文参考文献.docVIP

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HNF4alpha and HNF1alpha Dysfunction as a Molecular Rational for Cyclosporine Induced Posttransplantation Diabetes Mellitus 英文参考文献.doc

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HNF4alpha and HNF1alpha Dysfunction as a Molecular Rational for Cyclosporine Induced Posttransplantation Diabetes Mellitus 英文参考文献

HNF4alphaandHNF1alphaDysfunctionasaMolecular RationalforCyclosporineInducedPosttransplantation DiabetesMellitus Ju¨rgenBorlak1,2*,MonikaNiehof1 1Fraunhofer Institute of Toxicology and Experimental Medicine, Medical School of Hannover, Hannover, Germany, 2Center of Molecular Medicine and Medical BiotechnologyandCenterofPharmacologyandToxicology,MedicalSchoolofHannover,Hannover,Germany Abstract Posttransplantation diabetes mellitus (PTDM) is a frequent complication in immunosuppressive therapy. To better understand the molecular events associated with PTDM we investigated the effect of cyclosporine on expression and activityofhepaticnuclearfactor(HNF)1alphaand4alphaandongenescodingforglucosemetabolisminculturesoftherat insulinomacelllineINS-1E,thehumanepithelialcelllineCaco-2andwithZuckerdiabeticfatty(ZDF)rats.Inthepancreasof untreatedbutdiabeticanimalsexpressionofHNF4alpha,insulin1,insulin2andofphosphoenolpyruvatecarboxykinasewas significantlyrepressed.Furthermore,cyclosporinetreatmentoftheinsulinoma-1Ecelllineresultedinremarkablereduction inHNF4alphaproteinandINS1aswellasINS2geneexpression,whiletranscriptexpressionofHNF4alpha,apolipoprotein C2,glycerolkinase,pyruvatekinaseandaldolaseBwasrepressedintreatedCaco-2cells.Furthermore,withnuclearextracts ofcyclosporinetreatedcelllinesproteinexpressionandDNAbindingactivityofhepaticnuclearfactorswassignificantly repressed. As cyclosporine inhibits the calcineurin dependent dephosphorylation of nuclear factor of activated T-cells (NFAT) we also searched for binding sites for NFAT in the pancreas specific P2 promoter of HNF4alpha. Notably, we observedrepressedNFATbindingtoanovelDNAbindingsiteintheP2promoterofHNF4alpha.Thus,cyclosporinecaused inhibition of DNA binding of two important regulators for insulin signaling, i.e. NFAT and HNF4alpha. We further investigated HNF4alpha transcript expression and observed .200-fold differences in abundance in n=14 patients. Such variabilityinexpressionmighthelptoidentifyindividualsatrisk