奥美沙坦减轻高脂饮食诱导的非酒精性脂肪肝病的机制研究

Protective effects of olmesartan on high fat diet-induced nonalcoholic steatohepatitis in mice

目的探讨奥美沙坦对于高脂诱导的非酒精性脂肪肝病(NAFLD)的影响及可能机制。方法健康雄性8周龄C57BL/6小鼠24只随机分为高脂组(n=16)和正常饮食组(n=8),高脂组小鼠高脂饮食(60%的脂肪)12w后再随机分为高脂饮食对照组(n=8)、高脂饮食治疗组(n=8)。高脂饮食治疗组小鼠给予0.75mg/kg/d的奥美沙坦灌胃8w,灌胃结束后处理小鼠,留取空腹血样本检测AST和ALT。肝组织冰冻切片行油红O染色观察脂肪变;石蜡切片行HE和F4/80免疫组化染色观察肝脏炎症变化;实时荧光定量PCR检测肝脏TNF-α和IL-6mRNA的表达水平;Western Blot检测肝组织中IκB-α、p-IκBα、NF-κB信号通路的活化。结果奥美沙坦显著抑制了高脂诱导的NAFLD脂肪变性,并明显改善肝功能。实时荧光定量PCR结果表明奥美沙坦能显著降低肝脏组织中TNF-α和IL-6mRNA表达水平(P<0.05);Western Blot结果显示奥美沙坦显著抑制肝脏NF-κB信号通路活化。结论奥美沙坦显著抑制NAFLD小鼠肝脏炎性病变而保护肝功能,其机制与抑制NF-κB信号通路活化以及降低肝脏TNF-α和IL-6mRNA水平有关。

Objective To study the effects and possible mechanisms of Olmensartan, an AT1R blocker on the inflammation response,in a mouse model of nonalcoholic fatty liver disease （NAFLD）. Methods 24 male C57BL/6 mice of 8 weeks were randomly divided into a normal diet group and a high fat diet （HFD） group. Mice in the HFD group were given high fat diet for 12 weeks and further divided into a high fat diet control group and a high fat diet treatment group. For 8 weeks,along with the same access to high fat diet, the treatment group received 0.75mg/kg/d Olmesartan by gavage. All animals were killed after gavage was over. Serum was obtained to evaluate ALT,AST and TG levels. Livers were obtained for morphology （HE, Oil red O）, immunohistochemistry （F4/80）, Real-time PCR and Western blot analysis. Results Olmesartan had benefitical effects on high fat diet-induced hepatic steatosis and inflammation, and dramatically improved liver function. Increased expression levels of TNF-α and IL-6 mRNA were reduced and the NF-κB pathway activation was inhibited in liver by Olmesartan. Conclusion Olmesartan reduce hepatic lipid accumulation and inflammation in NAFLD. The mechanisms may be related with inhibiting NF- zB activation and reducing liver TNF-α and IL-6 expression.