p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor α: A potential role in the cardiac metabolic stress response

Philip M. Barger, Alyssa C. Browning, Ashley N. Garner, Daniel P. Kelly

Research output: Contribution to journalArticlepeer-review

241 Scopus citations

Abstract

The expression of enzymes involved in fatty acid β-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 α (PPARα). Evidence has emerged that PPARα 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 PPARα 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 NH2terminal A/B domain of the protein. Transient transfection studies in cardiac myocytes and in CV-1 cells utilizing homologous and heterologous PPARα target element reporters and mammalian one-hybrid transcription assays revealed that p38 MAPK phosphorylation of PPARα significantly enhanced ligand-dependent transactivation. Cotransfection studies performed with several known coactivators of PPARα 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 PPARα as a downstream effector of p38 kinase-dependent stress-activated signaling in the heart, linking extracellular stressors to alterations in energy metabolic gene expression.

Original languageEnglish
Pages (from-to)44495-44501
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number48
DOIs
StatePublished - Nov 30 2001

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