Abstract-Long-chain fatty acids (FA) coordinately induce the expression of a panel of genes involved in cellular FA metabolism in cardiac muscle cells, thereby promoting their own metabolism. These effects are likely to be mediated by peroxisome proliferator-activated receptors (PPARs). Whereas the significance of PPAR␣ in FA-mediated expression has been demonstrated, the role of the PPAR␤/␦ and PPAR␥ isoforms in cardiac lipid metabolism is unknown. To explore the involvement of each of the PPAR isoforms, neonatal rat cardiomyocytes were exposed to FA or to ligands specific for either PPAR␣ (Wy-14,643), PPAR␤/␦ (L-165041, GW501516), or PPAR␥ (ciglitazone and rosiglitazone). Their effect on FA oxidation rate, expression of metabolic genes, and muscle-type carnitine palmitoyltransferase-1 (MCPT-1) promoter activity was determined. Consistent with the PPAR isoform expression pattern, the FA oxidation rate increased in cardiomyocytes exposed to PPAR␣ and PPAR␤/␦ ligands, but not to PPAR␥ ligands. Likewise, the FA-mediated expression of FA-handling proteins was mimicked by PPAR␣ and PPAR␤/␦, but not by PPAR␥ ligands. As expected, in embryonic rat heart-derived H9c2 cells, which only express PPAR␤/␦, the FA-induced expression of genes was mimicked by the PPAR␤/␦ ligand only, indicating that FA also act as ligands for the PPAR␤/␦ isoform. In cardiomyocytes, MCPT-1 promoter activity was unresponsive to PPAR␥ ligands. However, addition of PPAR␣ and PPAR␤/␦ ligands dose-dependently induced promoter activity. Collectively, the present findings demonstrate that, next to PPAR␣, PPAR␤/␦, but not PPAR␥, plays a prominent role in the regulation of cardiac lipid metabolism, thereby warranting further research into the role of PPAR␤/␦ in cardiac disease.

It has been postulated that the failing heart suffers from chronic energy starvation, and that derangements in cardiac energy conversion are accessory to the progressive nature of this disease. The molecular mechanisms driving this 'metabolic remodelling' process and their significance for the development of cardiac failure are still open to discussion. Next to changes in mitochondrial function, the hypertrophied heart is characterized by a marked shift in substrate preference away from fatty acids towards glucose. It has been argued that the decline in fatty acid oxidation is not fully compensated for by a rise in glucose oxidation, thereby imposing an additional burden on overall ATP generating capacity. Several lines of evidence suggest that these metabolic adaptations are brought about, at least in part, by alterations in the rate of transcription of genes encoding for proteins involved in substrate transport and metabolism. Here, the principal metabolic changes are reviewed and the various molecular mechanisms that are likely to play a role are discussed. In addition, the potential significance of these changes for the aetiology of heart failure is evaluated.