Roxane Mansouri | PubMed Health

PubMed2004

Different ways to regulate the PPARalpha stability.

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-activated transcription factor. PPARalpha regulates lipid and glucose metabolism and controls the inflammatory response. Recently, we have shown that PPARalpha is a short-lived protein degraded by the ubiquitin-proteasome system. In this study, we have analysed the effects of interaction with RXRalpha, CBP, and N-CoR and also the implication of phosphorylation on ubiquitination and stability of PPARalpha. Our results show that interaction of PPARalpha with RXRalpha or CBP leads to an increase in the turnover of the protein. In contrast, interaction with the corepressor N-CoR, which inhibits its transcriptional activity, leads to a stabilization of the protein. Interestingly, treatment of cells with an inhibitor of Ser/Thr phosphatases known to lead to hyperphosphorylation of PPARalpha induces its transcriptional activity which is accompanied by a stabilization of the protein. These data indicate that heterodimerization, recruitment of cofactors, and post-translational modifications can modulate the stability of PPARalpha.

Animals↗

PubMed2004

The protein kinase C signaling pathway regulates a molecular switch between transactivation and transrepression activity of the peroxisome proliferator-activated receptor alpha.

Peroxisome proliferator-activated receptor (PPAR) alpha is a nuclear receptor implicated in several physiological processes such as lipid and lipoprotein metabolism, glucose homeostasis, and the inflammatory response. PPARalpha is activated by natural fatty acids and synthetic compounds like fibrates. PPARalpha activity has been shown to be modulated by its phosphorylation status. PPARalpha is phosphorylated by kinases such as the MAPKs and cAMP-activated protein kinase A. In this report, we show that protein kinase C (PKC) inhibition impairs ligand-activated PPARalpha transcriptional activity. Furthermore, PKC inhibition decreases PPARalpha ligand-induction of its target genes including PPARalpha itself and carnitine palmitoyltransferase I. By contrast, PKC inhibition enhances PPARalpha transrepression properties as demonstrated using the fibrinogen-beta gene as model system. Finally, PKC inhibition decreases PPARalpha phosphorylation activity of hepatocyte cell extracts. In addition, PPARalpha purified protein is phosphorylated in vitro by recombinant PKCalpha and betaII. The replacement of serines 179 and 230 by alanine residues reduces the phosphorylation of the PPARalpha protein. The PPARalpha S179A-S230A protein displays an impaired ligand-induced transactivation activity and an enhanced trans-repression activity. Altogether, our data indicate that the PKC signaling pathway acts as a molecular switch dissociating the transactivation and transrepression functions of PPARalpha, which involved phosphorylation of serines 179 and 230.

Alanine↗