Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha associated with age-dependent cardiac toxicity

The peroxisome proliferator-activated receptor alpha (PPAR alpha) is a memb er of the nuclear receptor superfamily and mediates the biological effects of peroxisome proliferators, To determine the physiological role of PPAR al pha in cardiac fatty acid metabolism, we examined the regulation of express ion of cardiac fatty acid-metabolizing proteins using PPAR alpha-null mice. The capacity for constitutive myocardial beta-oxidation of the medium and long chain fatty acids, octanoic acid and palmitic acid, was markedly reduc ed in the PPAR alpha-null mice as compared with the wild-type mice, indicat ing that mitochondrial fatty acid catabolism is impaired in the absence of PPAR alpha. In contrast, constitutive beta-oxidation of the very long chain fatty acid, lignoceric acid, did not differ between the mice, suggesting t hat the constitutive expression of enzymes involved in peroxisomal beta-oxi dation is independent of PPAR alpha. Indeed, PPAR alpha-null mice had norma l levels of the peroxisomal beta-oxidation enzymes except the D-type bifunc tional protein. At least seven mitochondrial fatty acid-metabolizing enzyme s were expressed at much lower levels in the PPAR alpha-null mice, whereas other fatty acid-metabolizing enzymes were present at similar or slightly l ower levels in the PPAR alpha-null, as compared with wild-type mice. Additi onally, lower constitutive mRNA expression levels of fatty acid transporter s were found in the PPAR alpha-null mice, suggesting a role for PPAR alpha in fatty acid transport and catabolism. Indeed, in fatty acid metabolism ex periments in vivo, myocardial uptake of iodophenyl 9-methylpentadecanoic ac id and its conversion to 3-methyl-nonanoic acid were reduced in the PPAR al pha-null mice. Interestingly, a decreased ATP concentration after exposure to stress, abnormal cristae of the mitochondria, abnormal caveolae, and fib rosis were observed only in the myocardium of the PPAR alpha-null mice. The se cardiac abnormalities appeared to proceed in an age-dependent manner. Ta ken together, the results presented here indicate that PPAR alpha controls constitutive fatty acid oxidation, thus establishing a role for the recepto r in cardiac fatty acid homeostasis, Furthermore, altered expression of fat ty acid-metabolizing proteins seems to lead to myocardial damage and fibros is, as inflammation and abnormal cell growth control can cause these condit ions.