A dominant negative human peroxisome proliferator-activated receptor (PPAR)α is a constitutive transcriptional corepressor and inhibits signaling through all PPAR isoforms

Several missense mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor ( PPAR) gamma have been described in subjects with dominantly inherited severe insulin resistance associated with partial lipodystrophy, hypertension, and dyslipidemia. These mutant receptors behave as dominant-negative inhibitors of PPAR gamma signaling when studied in transfected cells. The extent to which such dominant-negative effects extend to signaling through other coexpressed PPAR isoforms has not been evaluated. To examine these issues further, we have created a PPAR alpha mutant harboring twin substitutions, Leu459Ala and Glu462Ala, within the ligand binding domain ( PPAR alpha(mut)), examined its signaling properties, and compared the effects of dominant-negative PPAR alpha and PPAR gamma mutants on basal and ligand-induced gene transcription in adipocytes and hepatocytes. PPAR alpha(mut) was transcriptionally inactive, repressed basal activity from a PPAR response element-containing promoter, inhibited the coactivator function of cotransfected PPAR-gamma coactivator 1 alpha, and strongly inhibited the transcriptional response to cotransfected wild-type receptor. In contrast to PPAR gamma, wild-type PPAR alpha failed to recruit the transcriptional corepressors NCoR and SMRT. However, PPAR alpha(mut) avidly recruited these corepressors in a ligand-dissociable manner. In hepatocytes and adipocytes, both PPAR alpha(mut) and the corresponding PPAR gamma mutant were capable of inhibiting the expression of genes primarily regulated by PPAR alpha, -gamma, or -delta ligands, albeit with some differences in potency. Thus, dominant-negative forms of PPAR alpha and PPAR gamma are capable of interfering with PPAR signaling in a manner that 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.