MEK抑制剂PD98059对大鼠非酒精性脂肪性肝病的影响

The effects of MEK inhibitor PD98059 on nonalcoholic fatty liver disease in rats

目的观察MEK抑制剂PD98059对大鼠非酒精性脂肪性肝病(NAFLD)的影响及可能机制。方法应用高脂饮食复制非酒精性脂肪性肝病模型。32只雄性Wister大鼠随机分成正常对照组(N组)、PD98059+普通饲料组(P组)、高脂模型组(M组)和PD98059+高脂组(PM组)共4组,每组8只。于分组喂养的第4、6、8周末分别给予P组和PM组大鼠鼠尾静脉注射MEK抑制剂PD98059干预。10周末结束实验,检测血清丙氨酸转移酶(ALT)、门冬氨酸转移酶(AST)、甘油三酯(TG)、总胆固醇(TC)、极低密度脂蛋白(VLDL),肝组织TG、TC、丙二醛(MDA)、超氧化物歧化酶(SOD);光镜观察大鼠肝脏的病理改变,免疫组化法检测肝脏磷酸化细胞外信号调节激酶1/2(p-ERK1/2)表达。结果与N组比较,P组血清转氨酶、血脂、肝组织TG、TC、MDA、SOD以及肝脏病理学和p-ERK1/2表达无明显差异(P>0.05),M组所有大鼠肝细胞脂肪变性范围均超过50%并伴有不同程度的炎性细胞浸润和坏死,p-ERK1/2表达增强,ALT、AST、TC、肝组织TG、TC、MDA显著升高,SOD明显降低(P<0.05,P<0.01)。与M组比较,PM组p-ERK1/2表达减少(P<0.01),ALT、肝组织TG、TC、MDA降低,SOD升高(P<0.05,P<0.01),同时大鼠的肝脏病理学得到了改善。结论PD98059通过抑制MEK/ERK信号通路对非酒精性脂肪性肝病大鼠发挥保护作用。

Objective To investigate the effects of MEK inhibitor PD98059 on nonalcoholic fatty liver disease （NAFLD） in rats and its possible mechanism. Methods The NAFLD model of rats was duplicated with high-fat diet. Thirty-two male Wister rats were randomly divided into normal control group （group N）, PD98059 and common diet group （group P）, high-fat model group（ group M）and PD98059 and high-fat diet group（ group PM） with 8 for each group. At the end of 4,6 ,and 8 weeks, the rats were given a tail vein injection of either PD98059 （0.3 mg/ kg, group P and group PM） or the relative solvent （group N and group M）. The serum alanine aminotransferase （ ALT）, aspartate aminotransferase （ AST）, triglycerides （ TG）, total cholesterol （ TC ）, very low density lipoprotein （VLDL） and the level of liver tissue homogenates TG, TC, malondialdehyde （ MDA）, superoxide dismutase（SOD） were measured by biochemical methods. Histopathological change in liver was observed. The expression of phos- phorylated extracellular-regulated kinasel/2 （p-ERK1/2） in liver was detected by immunohistochemistry. Results There were no significant differences between group N and group P in all indexs. Compared with group N, the group M developed over 50% steatosis,with inflammation cell infiltration and necrosis, the serum ALT, AST, TC,VLDL ,the level of liver tissue homogenates TC,TG,MDA and the expression of p-ERK1/2 in liver markedly increased, simultaneously with significantly decreased on liver tissue homogenates SOD （P 〈 0.01, P 〈 0.05 ）. Compared with group M, the expression of p-ERK1/2 ,the serum ALT and the level of liver tissue homogenates TG,TC,and MDA decreased in group PM, while the level of liver tissue homogenates SOD increased （ P 〈 0. 01, P 〈 0. 05 ）. His- topathological change in liver of group PM ameliorated. Conclusion PD98059 may ameliorate NAFLD in rats by inhibiting the MEK/ERK signal pathway.