PPAR signaling in the control of cardiac energy metabolism

Cardiac energy metabolic shifts occur as a normal response to diverse physi ologic and dietary conditions and as a component of the pathophysiologic pr ocesses which accompany cardiac hypertrophy, heart failure, and myocardial ischemia. The capacity to produce energy via the utilization of fats by the mammalian postnatal heart is controlled in part of the level of expression of nuclear genes encoding enzymes involved in mitochondrial fatty acid bet a -oxidation (FAO). The principal transcriptional regulator of FAO enzyme g enes is the peroxisome proliferator-activated receptor alpha (PPAR alpha), a member of the ligand-activated nuclear receptor superfamily. Among the li gand activators of PPAR alpha are long-chain fatty acids; therefore, increa sed uptake of fatty acid substrate into the cardiac myocyte induces a trans criptional response leading to increased expression of FAO enzymes. PPAR al pha -mediated control of cardiac metabolic gene expression is activated dur ing postnatal development, short-term starvation, and in response to exerci se training. In contrast, certain pathophysiologic states, such as pressure overload-induced hypertrophy, result in deactivation of PPAR alpha and sub sequent dysregulation of FAO enzyme gene expression, which sets the stage f or abnormalities in cardiac lipid homeostasis and energy production, some o f which are influenced by gender. Thus, PPAR alpha not only serves a critic al role in normal cardiac metabolic homeostasis, but alterations in PPAR al pha signaling likely contribute to the pathogenesis of a variety of disease states. PPAR alpha as a ligand-activated transcription factor is a potenti al target for the development of new therapeutic strategies aimed at the pr evention of pathologic cardiac remodeling. (Trends Cardiovasc Med 2000;10:2 38-245). (C) 2001 Elsevier Science Inc.