Regulation of Peroxisome Proliferator-Activated Receptors by E6-Associated Protein

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors (NRs) that regulate genes involved in lipid and glucose metabolism. PPAR activity is regulated by interactions with cofactors and of interest are cofactors with ubiquitin ligase activity. The E6-associated protein (E6-AP) is an E3 ubiquitin ligase that affects the activity of other NRs, although its effects on PPARs have not been examined. E6-AP inhibited the ligand-independent transcriptional activity of PPAR α and PPAR β , with marginal effects on PPAR γ , and decreased basal mRNA levels of PPAR α target genes. Inhibition of PPAR α activity required the ubiquitin ligase function of E6-AP, but occurred in a proteasome-independent manner. PPAR α interacted with E6-AP, and in mice treated with PPAR α agonist clofibrate, mRNA and protein levels of E6-AP were increased in wildtype, but not in PPAR α null mice, indicating a PPAR α -dependent regulation. These studies suggest coordinate regulation of E6-AP and PPAR α , and contribute to our understanding of the role of PPARs in cellular metabolism.