COX‐2 induction in mice with experimental nutritional steatohepatitis

Abstract

The underlying mechanisms that perpetuate liver inflammation in nonalcoholic steatohepatitis are poorly understood. We explored the hypothesis that cyclooxygenase-2 (COX-2) can exert pro-inflammatory effects in metabolic forms of fatty liver disease. Male wild-type (WT) C57BL6/N or peroxisome proliferator–activated receptor α knockout (PPAR-α−/−) mice were fed a lipogenic, methionine- and choline-deficient (MCD) diet or the same diet with supplementary methionine and choline (control). COX-2 was not expressed in livers of mice fed the control diet. In mice fed the MCD diet, hepatic expression of COX-2 messenger RNA and protein occurred from day 5, continued to rise, and was 10-fold higher than controls after 5 weeks, thereby paralleling the development of steatohepatitis. Upregulation of COX-2 was even more pronounced in PPAR-α−/− mice. Induction of COX-2 was completely prevented by dietary supplementation with the potent PPAR-α agonist Wy-14,643 in WT but not PPAR-α−/− mice. COX-2 upregulation was preceded by activation of nuclear factor κB (NF-κB) and coincided with increased levels of tumor necrosis factor α (TNF-α), interleukin (IL)-6, and intercellular adhesion molecule 1 (ICAM-1). Selective COX-2 inhibitors (celecoxib and NS-398) protected against the development of steatohepatitis in WT but not PPAR-α−/− mice. In conclusion, induction of COX-2 occurs in association with NF-κB activation and upregulation of TNF-α, IL-6, and ICAM-1 in MCD diet–induced steatohepatitis. PPAR-α suppresses both COX-2 and development of steatohepatitis, while pharmacological inhibition of COX-2 activity ameliorates the severity of experimental steatohepatitis. COX-2 may therefore be a pro-inflammatory mediator in metabolic forms of steatohepatitis. (HEPATOLOGY 2006;43:826–836.)