环氧化酶-2在非酒精性脂肪性肝炎大鼠发病中的作用

Cyclooxygenase-2 may impact the development of nonalcoholic steatohepatitis by insulin signaling pathway

目的探讨环氧化酶-2(COX-2)在非酒精性脂肪性肝炎(NASH)发病中的作用。方法建立高脂饮食大鼠NASH模型,应用免疫组织化学方法和原位杂交方法,研究COX-2在大鼠NASH肝组织的表达状况,以及肝组织内胰岛素信号传导关键分子,包括胰岛素受体(ISR),胰岛素受体底物(IRS),磷脂酰肌醇3激酶(PI3K),蛋白激酶B(AKT)等的变化。采用SPSS 11.5统计软件包进行统计分析,one way ANOVA法进行组间方差分析,Pearson法进行相关分析。结果成功建立了高脂饮食大鼠NASH模型,COX-2在NASH大鼠肝组织内表达明显上调,并与HOMA-IR密切相关(r=0.838,P=0.018;r=0.746,P=0.023),肝组织内ISR、IRS和PI3K表达下调,与COX-2负相关(r=0.606,P=0.046;r=0.943,P=0.006;r=-0.807,P=0.022),肝组织内AKT表达上调,与COX-2正相关(r=0.692,P=0.035)。结论 COX-2可能通过影响胰岛素信号传导参与NASH发病过程,通过干预COX-2,可能为NASH治疗的新思路。

Objective To explore the role of cyclooxygenase-2 （COX-2） in pathogenesis of nonalcoholic steatohepatitis （NASH）. Methods SD rat induced by high-fat diet was built, and the expressions of COX-2 and COX-2 mRNA in liver tissues were detected by immunohistochemistry and in situ hybridization respectively. The key signaling molecules of insulin such as insulin receptor （ISR）, insulin receptor substance（IRS） and protein kinase B（AKT） in liver were also detected by immunohistochemistry. Results We successfully established a rat NASH model by high diet. The expression of COX-2 and COX-2 mRNA were increased in liver tissues from NASH model associated with HOMA-IR （r=0.838, P=0.018 and r=0.746, P=0.023 respectively）. The expressions of ISR, 1RS and PI3K were down-regulated （r=-0.606, P=0.046; r=-0.943, P=0.006 and r=-0.807, P=0.022 respectively）, on the contrary, the expression of AKT was up- regulated in liver tissues from NASH model. Further statistically analysis showed that the expression of ISR, IRS and PI3K were negative correlated with the expression of COX-2, while the expression of AKT was positively correlated with the expression of COX-2（r=0.692, P=0.035）. Conclusion COX-2 may involve in the development of NASH by affecting the insulin signaling pathway. It could offer a new view to treat NASH by impacting COX-2 way.