We explored the roles of nuclear factor-κB (NF-κB) and tumor necrosis factor (TNF) α (TNF-α) as mediators of inflammation in a nutritional model of steatohepatitis.

Wild-type (wt), TNF null (−/−), and TNF receptor (R)-1^−/− mice were fed a methionine- and choline-deficient (MCD) diet for up to 5 weeks. Liver injury (serum alanine aminotransferase [ALT]), hepatic inflammation, triglycerides, and lipid peroxide levels were determined. Hepatic NF-κB activation and expression of TNF and intercellular adhesion molecule-1 (ICAM-1) were assayed.

Irrespective of genotype, MCD diet-fed mice developed hepatic lipid peroxidation and serum ALT elevation; at day 10, livers from wt, TNF^−/−, and TNFR-1^−/− mice showed equivalent steatohepatitis. NF-κB/DNA binding was enhanced in hepatic nuclear fractions from MCD diet-fed wt mice compared with dietary controls; there were corresponding increases of ICAM-1 and TNF messenger RNA (mRNA). Likewise, NF-κB activation and ICAM-1 expression were enhanced by MCD dietary feeding in TNF^−/− and TNFR-1^−/− mice compared with respective controls. To establish whether NF-κB is a primary mediator of inflammation in experimental steatohepatitis, we over-expressed a mutant, nondegradable IκB (mIκB), delivered by adenovirus in vivo. As expected, hepatic mIκB expression reduced NF-κB/DNA binding induced by MCD dietary feeding, with resultant abrogation of ICAM-1 and TNF synthesis. Such blockade of NF-κB transcriptional activation substantially protected against development of steatohepatitis, with significant reductions in liver injury and hepatic inflammation.

In the MCD dietary model of steatohepatitis, NF-κB is activated early and is an important proinflammatory mediator of lesion development, but steatohepatitis occurs independently of TNF synthesis and TNFR-1 activation.