Activation of peroxisome proliferator-activated receptors (PPARs) by theirligands and protein kinase A activators

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 th ese receptors. We show here that activators of protein kinase A (PKA) can e nhance mouse PPAR activity in the absence and the presence of exogenous lig ands 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 d omains of PPAR can be phosphorylated by PKA in vitro. Moreover, gel retarda tion experiments suggest that PKA stabilizes binding of the liganded PPAR t o 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 PP ARs. 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 regul ated 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 mo del associating this pathway in the control of fatty acid beta -oxidation u nder conditions of fasting, stress, and exercise.