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Molecular Endocrinology 14 (12): 1962-1975
Copyright © 2000 by The Endocrine Society

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

Gwendal Lazennec, Laurence Canaple, Damien Saugy and Walter Wahli

INSERM U540 (G.L.) "Endocrinologie Moléculaire et Cellulaire des Cancers" 34090 Montpellier, France
Institut de Biologie Animale (G.L., L.C., D.S., W.W.) Université de Lausanne 1015 Lausanne, Switzerland

The nuclear peroxisome proliferator-activated receptors (PPARs) {alpha}, ß, 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 ß-oxidation under conditions of fasting, stress, and exercise.




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