Peroxisome proliferator-activated receptor-alpha (PPARα) belongs to the nuclear receptor (NR) family of transcription factors and regulates lipid and glucose metabolism. Like other NRs, the regulation of gene expression by PPARα depends on cofactor recruitment to the transcription complex and multiple protein-protein interactions. In this study, Murine Double Minute 2 (MDM2), an E3 ubiquitin ligase, is identified as a PPARα-interacting protein that regulates PPARα transcriptional activity. MDM2 modulated the transcriptional activity of PPARα and PPARβ/δ, but not PPARγ in reporter assays. Knockdown of MDM2 by small interfering RNA in rat hepatoma cells inhibited ligand-induced mRNA levels of several PPARα target genes involved in lipid metabolism. MDM2 associated with PPARα on target gene promoters, and this association increased in response to Wy14,643 treatment. MDM2 interacted with PPARα and this interaction occurred with the A/B domain of PPARα. Coexpression of MDM2 increased PPARα ubiquitination and the E3 ubiquitin ligase activity of MDM2 affected PPARα protein expression and transcriptional activity. MDM2 expression was decreased in response to clofibrate in wild-type (WT), but not in PPARα null mice, indicating a PPARα-dependent regulation. These studies identify a role for MDM2 in regulating PPARα-mediated pathways of lipid metabolism.
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