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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
COX-2 induction in mice with experimental nutritional steatohepatitis: Role as pro-inflammatory mediator
Hepatology, Volume 43, No. 4, Year 2006
Notification
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Description
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. Copyright © 2006 by the American Association for the Study of Liver Diseases.
Authors & Co-Authors
Yu, Jun
Australia, Sydney
The University of Sydney
Hong Kong
Prince of Wales Hospital Hong Kong
Ip, Emilia
Australia, Sydney
The University of Sydney
Dela Peña, Aileen
Australia, Sydney
The University of Sydney
Jing, Yun Hou
Australia, Sydney
The University of Sydney
Sesha, Jayshree
Australia, Sydney
The University of Sydney
Pera, Natasha
Australia, Sydney
The University of Sydney
Hall, Pauline De La M.
South Africa, Cape Town
Faculty of Health Sciences
Kirsch, Richard H.
South Africa, Cape Town
Faculty of Health Sciences
Leclercq, Isabelle
Belgium, Louvain-la-neuve
Université Catholique de Louvain
Farrell, Geoffrey C.
Australia, Sydney
The University of Sydney
Australia, Canberra
The Australian National University
Statistics
Citations: 166
Authors: 10
Affiliations: 5
Identifiers
Doi:
10.1002/hep.21108
ISSN:
02709139
Research Areas
Cancer
Noncommunicable Diseases
Participants Gender
Male