These findings indicate that dietary cholesterol, possibly in the form of modified plasma lipoproteins, is an important risk factor for the progression to hepatic inflammation in diet-induced NASH.

Fibroblast growth factor 21 is an endocrine factor, secreted mainly by the liver, that exerts metabolic actions that favour glucose metabolism. Its role in the heart is unknown. Here we show that Fgf21 À / À mice exhibit an increased relative heart weight and develop enhanced signs of dilatation and cardiac dysfunction in response to isoproterenol infusion, indicating eccentric hypertrophy development. In addition, Fgf21 À / À mice exhibit enhanced induction of cardiac hypertrophy markers and pro-inflammatory pathways and show greater repression of fatty acid oxidation. Most of these alterations are already present in Fgf21 À / À neonates, and treatment with fibroblast growth factor 21 reverses them in vivo and in cultured cardiomyocytes. Moreover, fibroblast growth factor 21 is expressed in the heart and is released by cardiomyocytes. Fibroblast growth factor 21 released by cardiomyocytes protects cardiac cells against hypertrophic insults. Therefore, the heart appears to be a target of systemic, and possibly locally generated, fibroblast growth factor 21, which exerts a protective action against cardiac hypertrophy.

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.