Phosphorylation of peroxisome proliferator-activated receptor alpha in rat Fao cells and stimulation by ciprofibrate

Biochem Pharmacol. 1999 Sep 15;58(6):1001-8. doi: 10.1016/s0006-2952(99)00182-3.


The basic mechanism(s) by which peroxisome proliferators activate peroxisome proliferator-activated receptors (PPARs) is (are) not yet fully understood. Given the diversity of peroxisome proliferators, several hypotheses of activation have been proposed. Among them is the notion that peroxisome proliferators could activate PPARs by changing their phosphorylation status. In fact, it is well known that several members of the nuclear hormone receptor superfamily are regulated by phosphorylation. In this report, we show that the rat Fao hepatic-derived cell line, known to respond to peroxisome proliferators, exhibited a high content of PPARalpha. Alkaline phosphatase treatment of Fao cell lysate as well as immunoprecipitation of PPARalpha from cells prelabeled with [32P] orthophosphate clearly showed that PPARalpha is indeed a phosphoprotein in vivo. Moreover, treatment of rat Fao cells with ciprofibrate, a peroxisome proliferator, increased the phosphorylation level of the PPARalpha. In addition, treatment of Fao cells with phosphatase inhibitors (okadaic acid and sodium orthovanadate) decreased the activity of ciprofibrate-induced peroxisomal acyl-coenzyme A oxidase, an enzyme encoded by a PPARalpha target gene. Our results suggest that the gene expression controlled by peroxisome proliferators could be mediated in part by a modulation of the PPARalpha effect via a modification of the phosphorylation level of this receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Oxidase
  • Animals
  • Cell Line
  • Clofibric Acid / analogs & derivatives*
  • Clofibric Acid / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Fibric Acids
  • Gene Expression Regulation / drug effects
  • Microbodies / drug effects
  • Microbodies / enzymology
  • Oxidoreductases / metabolism
  • Peroxisome Proliferators / pharmacology*
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Phosphorylation / drug effects
  • Rats
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Enzyme Inhibitors
  • Fibric Acids
  • Peroxisome Proliferators
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Clofibric Acid
  • Oxidoreductases
  • Acyl-CoA Oxidase
  • Phosphoric Monoester Hydrolases
  • ciprofibrate