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COX‐2 induction in mice with experimental nutritional steatohepatitis: Role as pro‐inflammatory mediator
Author(s) -
Yu Jun,
Ip Emilia,
dela Peña Aileen,
Hou Jing Yun,
Sesha Jayshree,
Pera Natasha,
Hall Pauline,
Kirsch Richard,
Leclercq Isabelle,
Farrell Geoffrey C.
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21108
Subject(s) - mediator , steatohepatitis , nonalcoholic steatohepatitis , inflammation , medicine , inflammatory response , fatty liver , disease , nonalcoholic fatty liver disease
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. I n 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. (H EPATOLOGY 2006;43:826–836.)