Modulation of Hepatic Mitochondrial Fat Oxidation and Hepatic Gene Transcription by Tumor Necrosis Factor

Abstract

Monocyte secretory mediators have been implicated in the regulation of metabolism following sepsis and trauma. Experimental evidence is increasing that cytokines are active in regulation of lipid metabolism at all levels. The regulation of hepatic fatty acid oxidation is dependent on the enzyme carnitine palmitoyltransferase (CPT), which has been described as the rate-limiting enzyme in hepatic mitochondrial β-oxidation of long-chain fatty acids. We hypothesized that tumor necrosis factor alpha (TNF-α) may modulate hepatic mitochondrial long-chain fatty acid oxidation and that this effect on fatty acid oxidation may be mediated by CPT gene transcriptional mechanisms. To investigate the effect of TNF-α on hepatic mitochondrial fatty acid oxidation and CPT gene expression, we studied TNF-α in vitro with respect to CPT gene transcription, CPT translation, and hepatic mitochondrial fatty acid oxidation to ketone bodies using either H4IIe rat hepatoma cell culture or rat hepatocytes in primary cell culture. Preliminary investigation suggested that TNF-α increased CPT mRNA in H4IIe rat hepatoma cell culture. To investigate the mechanism by which CPT gene expression is altered, we studied the role of protein kinase C or Ca2+ as mediators of the TNF-α effect on CPT gene transcription.