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.

Fatty acids are thought to play a role in the activity of uncoupling proteins (UCP) and have been shown to regulate the expression of genes encoding proteins involved in fatty acid handling. Therefore, we investigated whether fatty acids, which are the main substrates for the heart, affect rat cardiac UCP‐2 expression in vivo and in vitro. After birth, when the contribution of fatty acid oxidation to cardiac energy conversion increases, UCP‐2 expression enhanced rapidly. In the adult heart, however, UCP‐2 mRNA levels did not alter during conditions associated with either enhanced (fasting, diabetes) or decreased (hypertrophy) fatty acid utilization. Exposure of neonatal cardiomyocytes and embryonic rat heart‐derived H9c2 cells to fatty acids (palmitic and oleic acid) for 48 h strongly induced UCP‐2 expression. Stimulation of neonatal cardio‐myocytes with triiodothyronine also increased UCP‐2 mRNA levels, though only in the presence of fatty acids. Ligands specific to the fatty acid‐activated transcription factor PPARa, but not to PPAR7, acted as inducers of cardiomyocyte UCP‐2 expression. It is concluded that fatty acids promote UCP‐2 expression in neonatal cardiomyocytes, which might explain the rapid increase in UCP‐2 mRNA in the postnatal heart. However, UCP‐2 mRNA levels in the adult heart appear to be insensitive to changes in cardiac fatty acid handling under various pathological conditions.—van der Lee, K. A. J. M., Willemsen, P. H. M., van der Vusse, G. J., van Bilsen, M. Effects of fatty acids on uncoupling protein‐2 expression in the rat heart. FASEB J. 14, 495–502 (2000)