Celecoxib decreases fatty acid synthase expression via down-regulation of c-Jun N-terminal kinase-1.

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 E(2) 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.