Peroxisome proliferator-activated receptor (PPAR) α is a nuclear receptor implicated in several physiological processes such as lipid and lipoprotein metabolism, glucose homeostasis, and the inflammatory response. PPARα is activated by natural fatty acids and synthetic compounds like fibrates. PPARα activity has been shown to be modulated by its phosphorylation status. PPARα 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 PPARα transcriptional activity. Furthermore, PKC inhibition decreases PPARα ligand-induction of its target genes including PPARα itself and carnitine palmitoyltransferase I. By contrast, PKC inhibition enhances PPARα transrepression properties as demonstrated using the fibrinogen-β gene as model system. Finally, PKC inhibition decreases PPARα phosphorylation activity of hepatocyte cell extracts. In addition, PPARα purified protein is phosphorylated in vitro by recombinant PKCα and βII. The replacement of serines 179 and 230 by alanine residues reduces the phosphorylation of the PPARα protein. The PPARα 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 molec-ular switch dissociating the transactivation and transrepression functions of PPARα, which involved phosphorylation of serines 179 and 230.