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

The peroxisome proliferator-activated receptor alpha (PPAR alpha) is a member of the nuclear receptor superfamily and mediates the biological effects of peroxisome proliferators, To determine the physiological role of PPAR alpha in cardiac fatty acid metabolism, we examined the regulation of expression 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 reduced in the PPAR alpha-null mice as compared with the wild-type mice, indicating 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 that the constitutive expression of enzymes involved in peroxisomal beta-oxidation is independent of PPAR alpha. Indeed, PPAR alpha-null mice had normal levels of the peroxisomal beta-oxidation enzymes except the D-type bifunctional protein. At least seven mitochondrial fatty acid-metabolizing enzymes were expressed at much lower levels in the PPAR alpha-null mice, whereas other fatty acid-metabolizing enzymes were present at similar or slightly lower levels in the PPAR alpha-null, as compared with wild-type mice. Additionally, lower constitutive mRNA expression levels of fatty acid transporters 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 experiments in vivo, myocardial uptake of iodophenyl 9-methylpentadecanoic acid and its conversion to 3-methyl-nonanoic acid were reduced in the PPAR alpha-null mice. Interestingly, a decreased ATP concentration after exposure to stress, abnormal cristae of the mitochondria, abnormal caveolae, and fibrosis were observed only in the myocardium of the PPAR alpha-null mice. These cardiac abnormalities appeared to proceed in an age-dependent manner. Taken together, the results presented here indicate that PPAR alpha controls constitutive fatty acid oxidation, thus establishing a role for the receptor in cardiac fatty acid homeostasis, Furthermore, altered expression of fatty acid-metabolizing proteins seems to lead to myocardial damage and fibrosis, as inflammation and abnormal cell growth control can cause these conditions.