Long-chain fatty acid-induced changes in gene expression in neonatal cardiac myocytes

Long-chain fatty acids are the most important substrates for the heart. In addition, they have been shown to affect signalling pathways and gene expre ssion, To explore the effects of long-chain fatty acids on cardiac gene exp ression, neonatal rat ventricular myocytes were cultured for 48 h rath eith er glucose (10 mM), fatty acids (palmitic and oleic acid, 0.25 mM each), or a combination of both as exogenous substrates, Exposure to fatty acids (bo th in the absence or presence of glucose) neither affected cellular morphol ogy and protein content nor induced alterations in the expression of phenot ypic marker genes like atrial natriuretic factor and the Ca-ATPase SERCA2, However, incubation with fatty acids (with or without glucose) resulted in up to 4-fold increases of the mRNA levels of fatty acid translocase (FAT/CD 36), heart-type fatty acid-binding protein, acyl-CoA synthetase, and long-c hain acyl-CoA dehydrogenase, In contrast, the expression of genes coding fo r proteins involved in glucose uptake and metabolism, i,e,, glucose transpo rter GLUT4, hexokinase IT, and glyceraldehyde 3-phosphate dehydrogenase, re mained constant or even declined under these conditions. These changes corr esponded with a 60% increase in cardiomyocyte fatty acid oxidation capacity , Interestingly, the peroxisome proliferator-activated receptor-alpha (PPAR alpha)-ligand Wy 14,643, but not the PPAR gamma-ligand ciglitazone, also r esulted in increased mRNA levels of genes involved in fatty acid metabolism . In conclusion, fatty acids specifically and co-ordinately up-regulate tra nscription of genes coding for proteins involved in cardiac fatty acid tran sport and metabolism, most likely through activation of PPAR alpha.