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