胃袖状切除术上调循环Nrg4浓度抑制肝脏脂肪酸合成改善肥胖小鼠肝脏脂肪变性

Sleeve gastrectomy up-regulates circulating Nrg4 concentration,inhibits hepatic fatty acid synthesis and improves hepatic steatosis in obese mice

目的探究胃袖状切除术(SG)对肥胖小鼠外周循环中脂肪因子神经调节蛋白4(Nrg4)的影响,并探究Nrg4在SG改善肝脏脂肪变性中所介导的作用与机制。方法对肥胖模型小鼠分别进行假手术(n=3只)、SG(n=3只)及注射Nrg4过表达腺相关病毒(n=3只),观察小鼠体重、脂代谢指标及肝脏脂肪浸润情况的差异,并检测术后小鼠外周血中Nrg4的浓度差异,检测脂肪酸合成通路关键酶表达差异;构建Nrg4过表达的小鼠肝细胞,验证Nrg4对脂肪酸合成通路关键酶表达的影响,以及不同Nrg4表达水平的肝细胞内脂肪沉积差异;使用GraphPad Prism 9软件进行数据分析,各组计量资料数据以(x±s)表示,组间比较采用方差分析。P<0.05为差异有统计学意义。结果接受SG或Nrg4过表达腺病毒相关病毒干预的肥胖小鼠体重明显下降(P<0.0001),外周血总胆固醇(TC)与甘油三酯(TG)水平明显降低(TC:P<0.01,TG:P<0.05),肝脏脂肪浸润减轻,外周血中Nrg4浓度升高(SG:P<0.0001,Nrg4过表达:P<0.001),肝脏脂肪酸合酶(Fasn)与乙酰辅酶A羧化酶1(Acc1)表达下降(Fasn:P<0.0001,Acc1:P<0.05);Nrg4过表达肝细胞内Fasn与Acc1表达降低,脂质沉积少于假手术组。结论SG可升高外周循环中Nrg4浓度并由Nrg4介导肝脏脂肪酸合成减弱,从而改善肝脏脂质代谢紊乱。

Objective To explore the effects of gastric sleeve resection(SG)on adipokine neuregulin 4(Nrg4)in the peripheral circulation of obese mice,and to explore the role and mechanism of Nrg4 in the improvement of hepatic steatosis by SG.Methods Sham operation(n=3 mice),SG(n=3 mice)and NRG4-overexpressed adeno-associated virus(n=3 mice)were performed on obese model mice,respectively.Differences in body weight,lipid metabolism indexes and liver fat infiltration were observed,and differences in Nrg4 concentration in peripheral blood of mice after operation were detected,and differences in expression of key enzymes in fatty acid synthesis pathway were detected.Mouse hepatocytes with Nrg4 overexpression were constructed to verify the effect of Nrg4 on the expression of key enzymes in fatty acid synthesis pathway,and the differences in fat deposition in hepatocytes with different Nrg4 expression levels.GraphPad Prism 9 software was used for data analysis.Measurement data of each group were expressed as(x±s),and ANOVA was used for comparison between groups.P<0.05 was considered statistically significant.Results Obese mice that received SG or Nrg4 overexpression adenovirus-related virus intervention significantly decreased body weight(P<0.0001),peripheral blood total cholesterol(TC)and triglyceride(TG)levels were significantly decreased(TC:P<0.01,TG:P<0.05),liver fat infiltration was alleviated,and peripheral blood Nrg4 concentration was increased(SG:P<0.0001,Nrg4 overexpression:P<0.001),liver fatty acid synthase(Fasn)and acetyl-CoA carboxylase 1(Acc1)expression decreased(Fasn:P<0.0001,Acc1:P<0.05);The expression of Fasn and Acc1 in hepatocytes with Nrg4 overexpression decreased,and the lipid deposition was less than that in sham operation group.Conclusion SG can increase Nrg4 concentration in peripheral circulation and decrease liver fatty acid synthesis mediated by Nrg4,thus ameliorating liver lipid metabolism disorder.