PPAR signaling in the control of cardiac energy metabolism

Cardiac energy metabolic shifts occur as a normal response to diverse physiologic and dietary conditions and as a component of the pathophysiologic processes 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 at the level of expression of nuclear genes encoding enzymes involved in mitochondrial fatty acid β-oxidation (FAO). The principal transcriptional regulator of FAO enzyme genes is the peroxisome proliferator-activated receptor α (PPARα), a member of the ligand-activated nuclear receptor superfamily. Among the ligand activators of PPARα are long-chain fatty acids; therefore, increased uptake of fatty acid substrate into the cardiac myocyte induces a transcriptional response leading to increased expression of FAO enzymes. PPARα-mediated control of cardiac metabolic gene expression is activated during postnatal development, short-term starvation, and in response to exercise training. In contrast, certain pathophysiologic states, such as pressure overload-induced hypertrophy, result in deactivation of PPARα and subsequent dysregulation of FAO enzyme gene expression, which sets the stage for abnormalities in cardiac lipid homeostasis and energy production, some of which are influenced by gender. Thus, PPARα not only serves a critical role in normal cardiac metabolic homeostasis, but alterations in PPARα signaling likely contribute to the pathogenesis of a variety of disease states. PPARα as a ligand-activated transcription factor is a potential target for the development of new therapeutic strategies aimed at the prevention of pathologic cardiac remodeling.