Regulation of Peroxisome Proliferator-Activated Receptor-α by MDM2

Peroxisome proliferator-activated receptor-alpha (PPAR alpha) 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 PPAR alpha 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 PPAR alpha-interacting protein that regulates PPAR alpha transcriptional activity. MDM2 modulated the transcriptional activity of PPAR alpha and PPAR beta/delta, but not PPAR gamma in reporter assays. Knockdown of MDM2 by small interfering RNA in rat hepatoma cells inhibited ligand-induced mRNA levels of several PPAR alpha target genes involved in lipid metabolism. MDM2 associated with PPAR alpha on target gene promoters, and this association increased in response to Wy14,643 treatment. MDM2 interacted with PPAR alpha and this interaction occurred with the A/B domain of PPAR alpha. Coexpression of MDM2 increased PPAR alpha ubiquitination and the E3 ubiquitin ligase activity of MDM2 affected PPAR alpha protein expression and transcriptional activity. MDM2 expression was decreased in response to clofibrate in wild-type (WT), but not in PPAR alpha null mice, indicating a PPAR alpha-dependent regulation. These studies identify a role for MDM2 in regulating PPAR alpha-mediated pathways of lipid metabolism.