p38 Mitogen-activated Protein Kinase Activates Peroxisome Proliferator-activated Receptor α

Abstract

The expression of enzymes involved in fatty acid ␤-oxidation (FAO), the principal source of energy production in the adult mammalian heart, is controlled at the transcriptional level via the nuclear receptor peroxisome proliferator-activated receptor ␣ (PPAR␣). Evidence has emerged that PPAR␣ activity is activated as a component of an energy metabolic stress response. The p38 mitogen-activated protein kinase (MAPK) pathway is activated by cellular stressors in the heart, including ischemia, hypoxia, and hypertrophic growth stimuli. We show here that PPAR␣ is phosphorylated in response to stress stimuli in rat neonatal cardiac myocytes; in vitro kinase assays demonstrated that p38 MAPK phosphorylates serine residues located within the NH 2 -terminal A/B domain of the protein. Transient transfection studies in cardiac myocytes and in CV-1 cells utilizing homologous and heterologous PPAR␣ target element reporters and mammalian one-hybrid transcription assays revealed that p38 MAPK phosphorylation of PPAR␣ significantly enhanced ligand-dependent transactivation. Cotransfection studies performed with several known coactivators of PPAR␣ demonstrated that p38 MAPK markedly increased coactivation specifically by PGC-1, a transcriptional coactivator implicated in myocyte energy metabolic gene regulation and mitochondrial biogenesis. These results identify PPAR␣ as a downstream effector of p38 kinase-dependent stress-activated signaling in the heart, linking extracellular stressors to alterations in energy metabolic gene expression.The expression of enzymes involved in fatty acid ␤-oxidation (FAO), 1 the principal source of energy production in the adult mammalian heart, is tightly controlled at the transcriptional level during cardiac development and in response to physiologic and pathophysiologic stimuli (1-7). The nuclear receptor PPAR␣ has been shown to serve as a key transcriptional regulator of this energy metabolic pathway (Ref. 8; reviewed in Ref. 9). PPAR␣ is a member of the nuclear receptor superfamily of transcription factors and binds cognate response elements as an obligate heterodimer with the retinoid X receptor (RXR). PPAR␣ is ligand-activated by a variety of natural and synthetic agonists, including arachidonic acid derivatives, fibrates, and long-chain fatty acids: metabolic substrates for cardiac FAO enzymes. The important role played by PPAR␣ in cardiac metabolism is underscored by the marked reduction in the basal level of cardiac FAO enzyme gene expression in PPAR␣ Ϫ/Ϫ mice (10, 11), leading to reduced long-chain fatty acid uptake and oxidation (12).Evidence has emerged that PPAR␣ plays a critical role in the energy metabolic stress response in tissues that rely largely on mitochondrial fat oxidation for energy production, such as heart and liver. Under normal physiologic conditions, the expression of cardiac FAO enzyme genes are induced after a short term fast coincident with increased use of fatty acids for myocardial energy production (1, 3). In contrast, PPAR␣ Ϫ/Ϫ mice do not exhibit the expecte...

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