The effect of celecoxib on hepatic fatty changes induced by a high-fat diet in type 2 diabetic rats
제2형 당뇨병 백서에서 고지방식이에 의한 지방간변화에 대한 celecoxib의 효과
Dept. of Medical Science/박사
The precise effect of anti-inflammatory treatment in non-alcoholic fatty liver disease is not known. We explored the hypothesis that cyclooxygenase (COX)-2 inhibitor can prevent fatty liver changes in Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats fed a high-fat diet. The rats were separately fed standard or high-fat diets ad libitum for 5 weeks. Rats fed a high-fat diet were further divided into three subgroups treated with vehicle (saline)-, celecoxib (15 mg/kg/day)-, or rosiglitazone (4 mg/kg/day). OLETF rats treated with celecoxib or rosiglitazone showed decreases in plasma glucose concentrations after glucose loading as well as concentrations of total cholesterol, triglyceride, free fatty acids, and liver enzymes. OLETF rats fed a high-fat diet developed severe hepatic steatosis. In contrast, rats fed a high-fat diet and treated with celecoxib or rosiglitazone showed reduced steatosis. Both celecoxib and rosiglitazone treatments decreased the expression of tumor necrosis factor-α and nuclear factor-B in the liver and resulted in properties leading to decreased oxidative stress (decreased expression of p22phox and increase expression of manganese-superoxide dismutase). Finally, a 5-week high-fat diet significantly induced the expression of carnitine-palmitoyltransferase-1 and acyl-CoA oxidase, rate-limiting enzymes of -oxidation in mitochondria and peroxisome, respectively. Both celecoxib and rosiglitazone treatments also restored abnormally enhanced expression of these enzymes. In contrast, expression of fatty acid synthase was significantly reduced by a high-fat diet and was not altered by celecoxib or rosiglitazone. Furthermore, celecoxib, but not rosiglitazone, increased mitochondrial DNA quantity. Pharmacological inhibition of COX-2 prevents the development of steatosis in type 2 diabetic animal models. This effect was probably mediated through attenuation on activations of pro-inflammatory cytokines and oxidative stress, prevention of mitochondrial alteration, and restoration of dysregulated fatty acid metabolism.