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.