Down-regulated expression of PPARα target genes, reduced fatty acid oxidation and altered fatty acid composition in the liver of mice transgenic for hTNFα

The present study investigated the hepatic regulation of fatty acid metabolism in hTNF alpha transgenic mice. Reduced hepatic mRNA levels and activities of carnitine palmitoyltransferase-II (CPT-II) and mitochondrial HMG-CoA synthase were observed, accompanied by decreased fatty acid oxidation, fatty acyl-CoA oxidase and fatty acid synthase (FAS) activities and down-regulated gene expression of mitochondrial acetyl-CoA carboxylase 2 (ACC2). The mRNA levels of peroxisome proliferator-activated receptor alpha (PPAR alpha) and PPAR delta were reduced. The hepatic fatty acid composition was altered, with increased amounts of saturated and polyunsaturated fatty acids. The relative amounts of Delta(9) desaturated fatty acids were decreased, as was Delta(9) desaturase mRNA. The CPT-I mRNA level remained unchanged. The PPAR alpha targeted genes CPT-II and HMG-CoA synthase are potential regulators of mitochondrial fatty acid oxidation and ketogenesis in hTNF alpha transgenic mice, and the increased propionyl-CoA level found is a possible inhibitor of these processes. Reduced mitochondrial and peroxisomal fatty acid oxidation may explain the increased hepatic triglyceride level induced by TNF alpha. This is not due to de novo fatty acid synthesis as both FAS activity and gene expression of ACC2 were reduced. (c) 2005 Elsevier B.V. All rights reserved.