COX-2 induction in mice with experimental nutritional steatohepatitis: Role as pro-inflammatory mediator.

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 alpha knockout (PPAR-alpha-/-) 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-alpha-/- mice. Induction of COX-2 was completely prevented by dietary supplementation with the potent PPAR-alpha agonist Wy-14,643 in WT but not PPAR-alpha-/- mice. COX-2 upregulation was preceded by activation of nuclear factor kappaB (NF-kappaB) and coincided with increased levels of tumor necrosis factor alpha (TNF-alpha), 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-alpha-/- mice. In conclusion, induction of COX-2 occurs in association with NF-kappaB activation and upregulation of TNF-alpha, IL-6, and ICAM-1 in MCD diet-induced steatohepatitis. PPAR-alpha 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.

• Authors: Jun Yu, Emilia Ip, Aileen Dela Peña, Jing Yun Hou, Jayshree Sesha, Natasha Pera, Pauline Hall, Richard Kirsch, Isabelle Leclercq, Geoffrey C Farrell
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 43 Issue 4 Pg. 826-36 (Apr 2006) ISSN: 0270-9139 [Print] United States
• PMID: 16557554 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclooxygenase 2 Inhibitors
• Inflammation Mediators
• Interleukin-6
• NF-kappa B
• PPAR alpha
• Tumor Necrosis Factor-alpha
• Intercellular Adhesion Molecule-1
• Methionine
• Cyclooxygenase 2

Topics

• Animals
• Choline Deficiency
• Cyclooxygenase 2 (biosynthesis, metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Diet
• Enzyme Induction
• Fatty Liver (enzymology, etiology, pathology)
• Inflammation Mediators (metabolism)
• Intercellular Adhesion Molecule-1 (metabolism)
• Interleukin-6 (metabolism)
• Lipogenesis
• Liver (drug effects, enzymology, metabolism, pathology)
• Male
• Methionine (deficiency)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• PPAR alpha (deficiency, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)