The peroxisome proliferator-activated receptor alpha is a phosphoprotein: regulation by insulin

• Published in: Endocrinology (Philadelphia) 1996-10, Vol.137 (10), p.4499-4502
• Main Authors: Shalev, A, Siegrist-Kaiser, C A, Yen, P M, Wahli, W, Burger, A G, Chin, W W, Meier, C A
• Format: Article
• Language: English
• Subjects: Adipocytes; Animals; Cell Line; Humans; Immunoprecipitation; In vivo methods and tests; Insulin; Insulin - pharmacology; Lipid metabolism; Lipids; Okadaic acid; Orthophosphate; Peroxisome proliferator-activated receptors; Phosphoproteins - physiology; Phosphorylation; Phosphorylation - drug effects; Rats; Rats, Sprague-Dawley; Receptors; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Cytoplasmic and Nuclear - physiology; Sensitizing; Thiazolidinediones; Thyroid; Time dependence; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Factors - physiology; Transcription, Genetic - drug effects; Transfection; Vanadate
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.137.10.4499

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily implicated in adipocyte differentiation. The observations that PPAR alpha is a regulator of hepatic lipid metabolism and that the insulin-sensitizing thiazolidinediones are ligands for PPAR gamma suggest that cross-talk might exist between insulin signaling and PPAR activity, possibly through insulin-induced PPAR phosphorylation. Immunoprecipitation of endogenous PPAR alpha from primary rat adipocytes prelabeled with [32P]-orthophosphate and pretreated for 2 h with vanadate and okadaic acid demonstrated for the first time that PPAR alpha is a phosphoprotein in vivo. Treatment with insulin induced a time-dependent increase in PPAR phosphorylation showing a 3-fold increase after 30 min. Insulin also increased the phosphorylation of human PPAR alpha expressed in CV-1 cells. These changes in phosphorylation were paralleled by enhanced transcriptional activity of PPAR alpha and gamma. Transfection studies in CV-1 cells and HepG2 cells revealed a nearly 2-fold increase of PPAR activity in the presence of insulin. In contrast, insulin had no effect on the transcriptional activity of transfected thyroid hormone receptor in CV-1 cells, suggesting a PPAR-specific effect. Thus, insulin stimulates PPAR alpha phosphorylation and enhances the transcriptional activity of PPAR, suggesting that the transcriptional activity of this nuclear hormone receptor might be modulated by insulin-mediated phosphorylation.