二甲双胍减缓2型糖尿病小鼠非酒精性脂肪肝的作用

Ameliorate effect of metformin on ameliorates nonalcoholic fatty liver disease in type 2 diabetic mice

目的探讨二甲双胍对2型糖尿病(type 2 diabetes mellitus,T2DM)小鼠非酒精性脂肪肝(non alcohol fatty liver disease,NAFLD)的减缓作用及其机制。方法将20只2型糖尿病db/db小鼠随机分成糖尿病模型组和二甲双胍组,另选10只同周龄正常db/m小鼠为正常对照组。糖尿病模型组和正常对照组灌胃蒸馏水,二甲双胍组灌胃二甲双胍(0.16 g/kg),干预8周后处死取肝脏组织,观察组织形态学改变。免疫组化法和Western Blot法检测肝脏组织中腺苷酸活化蛋白激酶α1(AMP-activated protein kinaseα1,AMPKα1)、低氧诱导因子-1α(hypoxia inducible factor 1α,HIF-1α)、乙酰辅酶A羧化酶(acetyl coa carboxylase,ACC)的表达情况。结果糖尿病模型组出现弥漫性肝细胞大泡性脂肪变,二甲双胍组肝细胞脂肪变性情况较糖尿病模型组明显减轻,且AST、ALT水平明显降低(均P <0.01)。二甲双胍组AMPKα1蛋白表达水平和AMPKα1、ACC磷酸化水平明显高于其他组,而ACC、HIF-1α蛋白表达水平明显低于其他组(均P <0.01)。结论二甲双胍可能通过激活AMPK信号通路,促进ACC蛋白磷酸化,抑制HIF-1α进而达到减缓2型糖尿病小鼠NAFLD发生的作用。

Objective To investigate the ameliorate effect of metformin on nonalcoholic fatty liver(NAFLD in type 2 diabetic mice and its mechanism. Methods Twenty db/db mice with type 2 diabetes were randomly divided into diabetic model group and metformin group,and ten normal db/m mice of the same age were in normal control group. The diabetic model group and normal control group were given distilled water,and the metformin group was given intragastric administration of metformin(0.16 g/kg). After 8-weeks treatment,liver was obtained and observed the morphological changes of the tissue. Immunohistochemical method and Western blot were used to detect the expression levels of AMPKα1,ACC and HIF-1α in liver. Results Diffuse hepatic vesicular steatosis was found in the diabetic model group. The fatty degeneration of hepatocytes and the level of AST and ALT in metformin group were significantly reduced than that in the diabetic model group. The expression level of AMPKα1 protein and phosphorylation levels of AMPKα1 and ACC in metformin group were significantly higher than that of other groups,but the expression level of ACC and HIF-1α was significantly lower than that of other groups(all P < 0.01). Conclusions Metformin may ameliorate the development of NAFLD in type 2 diabetes mellitus by activating AMPK pathway,promoting the phosphorylation of ACC protein and suppress HIF-1α.