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ORIGINAL RESEARCH ARTICLE

Celecoxib Decreases Fatty Acid Synthase Expression via Down-Regulation of c-Jun N-Terminal Kinase-1

Suying Lu^* and Michael C. Archer^*,,1

^* Department of Nutritional Sciences and Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Canada M5S 3E2

To whom requests for reprints should be addressed at ¹ Department of Nutritional Sciences, University of Toronto, FitzGerald Building, 150 College Street, Toronto, Ontario M5S 3E2, Canada. E-mail: m.archer{at}utoronto.ca

Nonsteroidal anti-inflammatory drugs (NSAIDs) are inhibitors of cyclooxygenase (COX). Our previous observations that celecoxib, a COX-2-specific inhibitor, not only inhibits rat mammary carcinogenesis, but also decreases fat deposition in rats fed a high-fat diet, prompted us to determine whether celecoxib affects lipid metabolism. At 57 days of age, two groups of 10 female Sprague Dawley rats were pair-fed a high-fat diet with or without 1500 ppm celecoxib for 15 weeks. Compared with controls, celecoxib-treated rats had 44.4% less hepatic triglycerides and 22.6% less intra-abdominal adipose tissue mass. In the liver and adipose tissue of several genes involved in fat metabolism and mobilization that we measured, only fatty acid synthase (FAS) was significantly down-regulated by celecoxib treatment. There were no differences in the level of prostaglandin E₂ in these tissues, indicating that celecoxib decreases fat accumulation by down-regulating FAS through a COX-2–independent mechanism. Among the potential molecular targets by which celecoxib may regulate FAS expression, only c-Jun N-terminal kinase-1 (JNK1) was significantly down-regulated. Furthermore, a known inhibitor of JNK suppressed FAS expression in rat hepatocytes. Our observations suggest that celecoxib suppresses FAS expression and decreases fat accumulation by down-regulating JNK1.

Key Words: celecoxib • fatty acid synthase • c-Jun N-terminal kinase-1 • rat • high-fat diet

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