A dominant negative human PPARalpha is a constitutive transcriptional co-repressor and inhibits signaling through all PPAR isoforms.

@article{citeulike:87067, abstract = {Several missense mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor gamma (PPARgamma) have been described in subjects with dominantly-inherited severe insulin resistance associated with partial lipodystrophy, hypertension and dyslipidaemia. These mutant receptors behave as dominant-negative inhibitors of PPARgamma signaling when studied in transfected cells. The extent to which such dominant-negative effects extend to signaling through other co-expressed PPAR isoforms has not been evaluated. To examine these issues further we have created a PPARalpha mutant harboring twin substitutions - Leu459Ala and Glu462Ala - within the ligand binding domain (PPARalphamut), examined its signaling properties, and compared the effects of dominant-negative PPARalpha and PPARgamma mutants on basal and ligand-induced gene transcription in adipocytes and hepatocytes. PPARalphamut was transcriptionally inactive, repressed basal activity from a PPAR response element-containing promoter, inhibited the co-activator function of cotransfected PGC1alpha, and strongly inhibited the transcriptional response to co-transfected wild-type receptor. In contrast to PPARgamma, wild-type PPARalpha failed to recruit the transcriptional corepressors NCoR and SMRT. However PPARalphamut avidly recruited these corepressors in a ligand-dissociable manner. In hepatocytes and adipocytes both PPARalphamut and the corresponding PPARgamma mutant (PPARgammamut) were capable of inhibiting the expression of genes primarily regulated by PPARalpha, gamma or delta ligands, albeit with some differences in potency. Thus dominant-negative forms of PPARalpha and PPARgamma are capable of interfering with PPAR signaling in a manner which is not wholly restricted to their cognate target genes. These findings may have implications for the pathogenesis of human syndromes resulting from mutations in this family of transcription factors.}, address = {Department of Clinical Biochemistry, and Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK; INSERM U.508, Institut Pasteur de Lille, 1 du Pr. Calmette, 59019 LILLE Cedex, France; Metabolic Research Laboratory, OCDEM, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK; MRC-Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.}, author = {Semple, R K K. and Meirhaeghe, A and Vidal-Puig, A J J. and Schwabe, J W R W. and Wiggins, D and Gibbons, G F F. and Gurnell, M and Chatterjee, V K K K. and O'rahilly, S }, citeulike-article-id = {87067}, doi = {http://dx.doi.org/10.1210/en.2004-1405}, issn = {0013-7227}, journal = {Endocrinology}, keywords = {pparalpha}, month = {January}, posted-at = {2008-02-06 02:07:11}, priority = {2}, title = {A dominant negative human PPAR{alpha} is a constitutive transcriptional co-repressor and inhibits signaling through all PPAR isoforms.}, url = {http://dx.doi.org/10.1210/en.2004-1405}, year = {2005} }

TY - JOUR ID - citeulike:87067 L3 - citeulike-article-id:87067 TI - A dominant negative human PPAR{alpha} is a constitutive transcriptional co-repressor and inhibits signaling through all PPAR isoforms. JF - Endocrinology AD - Department of Clinical Biochemistry, and Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK; INSERM U.508, Institut Pasteur de Lille, 1 du Pr. Calmette, 59019 LILLE Cedex, France; Metabolic Research Laboratory, OCDEM, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK; MRC-Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. SN - 0013-7227 N2 - Several missense mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor gamma (PPARgamma) have been described in subjects with dominantly-inherited severe insulin resistance associated with partial lipodystrophy, hypertension and dyslipidaemia. These mutant receptors behave as dominant-negative inhibitors of PPARgamma signaling when studied in transfected cells. The extent to which such dominant-negative effects extend to signaling through other co-expressed PPAR isoforms has not been evaluated. To examine these issues further we have created a PPARalpha mutant harboring twin substitutions - Leu459Ala and Glu462Ala - within the ligand binding domain (PPARalphamut), examined its signaling properties, and compared the effects of dominant-negative PPARalpha and PPARgamma mutants on basal and ligand-induced gene transcription in adipocytes and hepatocytes. PPARalphamut was transcriptionally inactive, repressed basal activity from a PPAR response element-containing promoter, inhibited the co-activator function of cotransfected PGC1alpha, and strongly inhibited the transcriptional response to co-transfected wild-type receptor. In contrast to PPARgamma, wild-type PPARalpha failed to recruit the transcriptional corepressors NCoR and SMRT. However PPARalphamut avidly recruited these corepressors in a ligand-dissociable manner. In hepatocytes and adipocytes both PPARalphamut and the corresponding PPARgamma mutant (PPARgammamut) were capable of inhibiting the expression of genes primarily regulated by PPARalpha, gamma or delta ligands, albeit with some differences in potency. Thus dominant-negative forms of PPARalpha and PPARgamma are capable of interfering with PPAR signaling in a manner which is not wholly restricted to their cognate target genes. These findings may have implications for the pathogenesis of human syndromes resulting from mutations in this family of transcription factors. KW - pparalpha AU - Semple, R K AU - Meirhaeghe, A AU - Vidal-Puig, A J AU - Schwabe, J W R AU - Wiggins, D AU - Gibbons, G F AU - Gurnell, M AU - Chatterjee, V K K AU - O'rahilly, S PY - 2005/01/20/ UR - http://dx.doi.org/10.1210/en.2004-1405 ER -