Constitutive Regulation of Cardiac Fatty Acid Metabolism through Peroxisome Proliferator-activated Receptor α Associated with Age-dependent Cardiac Toxicity

Abstract

The peroxisome proliferator-activated receptor ␣ (PPAR␣) is a member of the nuclear receptor superfamily and mediates the biological effects of peroxisome proliferators. To determine the physiological role of PPAR␣ in cardiac fatty acid metabolism, we examined the regulation of expression of cardiac fatty acid-metabolizing proteins using PPAR␣-null mice. The capacity for constitutive myocardial ␤-oxidation of the medium and long chain fatty acids, octanoic acid and palmitic acid, was markedly reduced in the PPAR␣-null mice as compared with the wild-type mice, indicating that mitochondrial fatty acid catabolism is impaired in the absence of PPAR␣. In contrast, constitutive ␤-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 ␤-oxidation is independent of PPAR␣ . Indeed, PPAR␣-null mice had normal levels of the peroxisomal ␤-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␣-null mice, whereas other fatty acid-metabolizing enzymes were present at similar or slightly lower levels in the PPAR␣-null, as compared with wild-type mice. Additionally, lower constitutive mRNA expression levels of fatty acid transporters were found in the PPAR␣-null mice, suggesting a role for PPAR␣ 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-methylnonanoic acid were reduced in the PPAR␣-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␣-null mice. These cardiac abnormalities appeared to proceed in an age-dependent manner. Taken together, the results presented here indicate that PPAR␣ 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.

Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice

“…These are the first examples of genes involved in liver growth whose expression is regulated at a basal level by Ppar␣ and can be added to a growing list of mainly fatty acid metabolism genes dependent on Ppar␣ for expression. 40,41 Taken together, our results indicate that Ppar␣ plays a role in regulating genes important in hepatocyte proliferation induced by multiple stimuli. Moreover, the livers of Ppar␣-null mice appear more sensitive to hepatotoxicants because of defects in pathways important for hepatocyte growth.…”

Peroxisome proliferator-activated receptor α mediates enhancement of gene expression of cerebroside sulfotransferase in several murine organs

“…PPARα maintains the constitutive expression of genes for several enzymes that are involved in the mitochondrial fatty acid β-oxidation system, such as long-chain acyl-CoA synthetase, and PPARα activation induces gene expression of these enzymes and stimulates β-oxidation [11, [38][39][40][41][42][43]. Because the synthesis of sphingolipids is initiated by the transfer of L-serine onto activated long-chain fatty acids, such as palmitoyl-CoA, which arises from the reaction with long-chain acyl-CoA synthetase [44], PPARα presumably participates in the regulation of overall sphingolipid metabolism.…”

Aging-induced decrease in the PPAR-α level in hearts is improved by exercise training

“…In the present study, the model rats of CHF, of which mRNA expression of PPAR-␣ is downregulated in the heart, caused a decrease in mRNA expression of HAD and CPT-I, which are target genes of PPAR-␣. It has been reported that the lack of PPAR-␣ (PPAR-␣ Ϫ/Ϫ mice) caused decreases of enzyme activity and protein and mRNA expression in FA metabolic enzymes in the mouse heart (1,35). On the other hand, it has recently been reported that cardiac-specific overexpression of PPAR-␣ caused an increase in gene expression and enzyme activity of CPT-I by the increase in gene and protein expressions of PPAR-␣ in the mouse heart, thereby inducing increases in FA uptake and utilization in the mouse heart (8).…”