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.
Blanquart
Christophe
C
UR 545 Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille, 1 rue du Pr. Calmette, 59019 Lille, France.
Mansouri
Roxane
R
Paumelle
Réjane
R
Fruchart
Jean-Charles
JC
Staels
Bart
B
Glineur
Corine
C
D000409:Alanine / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005340:Fibrinogen / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D047493:PPAR alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
D004791:Enzyme Inhibitors; D008024:Ligands; D047493:PPAR alpha; D012333:RNA, Messenger; D012097:Repressor Proteins; D012694:Serine; D005340:Fibrinogen; D011493:Protein Kinase C; D000409:Alanine