Activation of Peroxisome Proliferator-Activated Receptors (PPARs) by Their Ligands and Protein Kinase A Activators

Mol Endocrinol. 2000 Dec;14(12):1962-75. doi: 10.1210/mend.14.12.0575.

Abstract

The nuclear peroxisome proliferator-activated receptors (PPARs) alpha, beta, and gamma activate the transcription of multiple genes involved in lipid metabolism. Several natural and synthetic ligands have been identified for each PPAR isotype but little is known about the phosphorylation state of these receptors. We show here that activators of protein kinase A (PKA) can enhance mouse PPAR activity in the absence and the presence of exogenous ligands in transient transfection experiments. Activation function 1 (AF-1) of PPARs was dispensable for transcriptional enhancement, whereas activation function 2 (AF-2) was required for this effect. We also show that several domains of PPAR can be phosphorylated by PKA in vitro. Moreover, gel retardation experiments suggest that PKA stabilizes binding of the liganded PPAR to DNA. PKA inhibitors decreased not only the kinase-dependent induction of PPARs but also their ligand-dependent induction, suggesting an interaction between both pathways that leads to maximal transcriptional induction by PPARs. Moreover, comparing PPAR alpha knockout (KO) with PPAR alpha WT mice, we show that the expression of the acyl CoA oxidase (ACO) gene can be regulated by PKA-activated PPAR alpha in liver. These data demonstrate that the PKA pathway is an important modulator of PPAR activity, and we propose a model associating this pathway in the control of fatty acid beta-oxidation under conditions of fasting, stress, and exercise.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Oxidase
  • Animals
  • Cell Line
  • Cholera Toxin / pharmacology
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / physiology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Ligands
  • Male
  • Mice
  • Mice, Knockout
  • Models, Genetic
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Pyrimidines / pharmacology
  • Receptors, Cytoplasmic and Nuclear / agonists
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Receptors, Retinoic Acid / physiology
  • Recombinant Fusion Proteins / metabolism
  • Retinoid X Receptors
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription Factors / agonists
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology
  • Transcriptional Activation* / drug effects

Substances

  • Ligands
  • Protein Isoforms
  • Pyrimidines
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Recombinant Fusion Proteins
  • Retinoid X Receptors
  • Trans-Activators
  • Transcription Factors
  • pirinixic acid
  • Cholera Toxin
  • Cyclic AMP
  • Oxidoreductases
  • peroxisomal acyl-CoA oxidase
  • Acyl-CoA Oxidase
  • Cyclic AMP-Dependent Protein Kinases