Peroxisome Proliferator-activated Receptor α (PPARα) Turnover by the Ubiquitin-Proteasome System Controls the Ligand-induced Expression Level of Its Target Genes

International audiencePeroxisome proliferator activated-receptor α (PPARα) is a ligand-activated transcription factor belonging to the nuclear receptor family. PPARα is implicated in the regulation of lipid and glucose metabolism and in the control of inflammatory response. Recently, it has been demonstrated that a number of nuclear receptors are degraded by the ubiquitin-proteasome pathway. Since PPARα exhibits a circadian expression rhythm and since PPARα is rapidly regulated under certain pathophysiological conditions such as the acute phase inflammatory response, we hypothesized that PPARα protein levels must be under tight control. Here, we studied the mechanisms controlling PPARα protein levels and their consequences on the transcriptional control of PPARα target genes. Using pulse-chase experiments, it is shown that PPARα is a short-lived protein and that addition of its ligands stabilizes this nuclear receptor. By transient cotransfection experiments using expression vectors for PPARα and hemagglutinin-tagged ubiquitin, it is demonstrated that PPARα protein is ubiquitinated and that its ligands decrease the ubiquitination of this nuclear receptor, thus providing a mechanism for the ligand-dependent stabilization observed in pulse-chase experiments. In addition, treatment with MG132, a selective proteasome inhibitor, increases the level of ubiquitinated PPARα and inhibits its degradation in transfected cells. Furthermore, MG132 treatment enhances the level of endogenous PPARα in HepG2 cells. Finally, transient transfection and quantitative reverse transcription-PCR show that inhibition of PPARα degradation increases its transcriptional activation and expression of target genes such as apoA-II and fatty acid transport protein (FATP). Taken together, these data demonstrate that PPARα is degraded by the ubiquitin-proteasome system in a ligand-dependent manner. Regulation of its degradation provides a novel regulatory mechanism of transcriptional activity of this nuclear receptor