Peroxisome Proliferator-Activated Receptor (PPAR) α and PPARβ/δ, but not PPARγ, Modulate the Expression of Genes Involved in Cardiac Lipid Metabolism

Abstract

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.

Activation of PPAR-δ in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids

“…Furthermore, the finding that the PPAR-α agonist WY14643 likewise inhibits glucose utilisation in isolated muscle, but to a quantitatively much smaller extent than GW501516, corroborates previous evidence that these two PPAR subtypes transduce similar effects, but that PPAR-δ is of predominant importance in native skeletal muscle of rodents [5,10]. The direct and marked impact of PPAR-δ on genes involved in lipid oxidation [5,8,18] suggests that the GW501516-induced increase in fatty acid utilisation could be the primary event, which gives rise to impairment of glucose utilisation via the well-known mutual inhibition of cellular glucose and fatty acid utilisation (glucose-fatty acid cycle) [20,21]. This interpretation is compatible with our demonstration that GW501516-induced inhibition of glucose utilisation does not persist when cellular glucose requirements increase because of insufficient fatty acid availability or deteriorated mitochondrial ATP synthesis through the direct uncoupling of oxidative phosphorylation by high concentrations of GW501516.…”

“…Since agonists of PPAR-δ and PPAR-α have similar effects on the expression of lipid regulatory genes and fatty acid oxidation in cultured myocytes [10,18], we examined the effects of the specific PPAR-α agonist WY14643 in the same protocol as that used with GW501516. At a range of concentrations that dose-dependently activates PPAR-α (0.1, 1 and 10 μmol/l) [19], WY14643 impaired glucose oxidation but had no further effects on glucose metabolism (Table 1).…”

Molecular characterization of a gilthead sea bream (Sparus aurata) muscle tissue cDNA for carnitine palmitoyltransferase 1B (CPT1B)

“…Although insulin is a clear candidate for mediating reduced CPT1B expression, PPARs have been shown to up-regulate CPT1 gene expression in mammals (Baldán et al, 2004, Gilde et al, 2003, Mescaró et al, 1998. The parallel examination of the expression of the three PPAR isotypes in this post-prandial experiment revealed a positive and strong correlation between the expression pattern of CPT1B and that of PPARβ in the white muscle and also the liver of sea bream.…”

“…It is currently well established that fatty acids, peroxisome proliferators, as well as physiological conditions such as feeding and fasting affect the expression of the CPT1 genes , Brandt et al, 1998. Key mediators of these processes are the peroxisome proliferator-activated receptors, PPAR (Baldán et al, 2004, Gilde et al, 2003, Mescaró et al, 1998, which have been described as transcription factors at the crossroads of diet and hormonal signalling (Desvergne et al, 1998).…”

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

“…Peroxisome proliferator‐activated receptor alpha (PPARα) plays an important role in myocardial substrate metabolism by regulating the transcription of genes involved in FA transport, esterification, and oxidation (Banke et al., 2010; Gilde et al., 2003). Increases in FA oxidation and uptake in diabetic hearts were significantly reduced in PPARα −/− mice (Campbell et al., 2002).…”