高脂饮食对法尼醇受体(FXR)敲除小鼠糖脂代谢及肝脏脂肪变性的影响研究

Effect of High Fat Diet on Glycolipid Metabolism and Hepatic Steatosis in Farnesoid X Receptor(FXR) Knockout Mice

目的探讨高脂饮食对法尼醇受体(farnesoid X receptor,FXR)敲除小鼠糖脂代谢及肝脏脂肪变性的影响。方法正常饮食(normal diet,ND)组:C57BL/6(wild type,WT)小鼠(n=6)和FXR-/-小鼠(n=6)给予辐照灭菌维持饲料喂养12周。高脂饮食(high fat diet,HFD)组:C57BL/6小鼠(n=6)和FXR-/-小鼠(n=6)给予45%高脂饲料喂养12周。小鼠处死后全自动生化分析仪检测血清总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)、高密度脂蛋白胆固醇(High density lipoprotein cholesterol,HDL-C)、谷丙转氨酶(alanine aminotransferase,ALT)、谷草转氨酶(aspartate aminotransferase,AST)和总胆汁酸(total bile acid,TBA)指标;RT-PCR检测肝脏炎症因子TNF-α、TLR4和FXR下游基因小分子异源二聚体(small heterodimer partner,SHP)、胆固醇7α-羟化酶(cholesterol 7α-hydroxylase,CYP7A1)的相对表达量;HE染色观察肝脏脂肪变性情况。结果高脂饮食喂养条件下,C57BL/6小鼠和FXR-/-小鼠体质量变化无差异,但相比C57BL/6小鼠,FXR-/-小鼠表现出更为严重糖耐量受损(P<0.01)、脂质代谢紊乱(P<0.01)、血清胆汁酸增高(P<0.01)、肝脏炎症(P<0.01)和肝脏脂肪变性。结论FXR的缺失引起小鼠糖脂代谢紊乱、胆汁酸代谢异常、肝脏脂肪变性,但这种改变需要高脂饮食的诱导。

Objective To investigate the effects of high fat diet on glycolipid metabolism and hepatic steatosis in farnesoid X receptor(FXR)knockout mice.Method Normal diet(ND)group:C57BL/6(wild type,WT)mice(n=6)and FXR-/-mice(n=6)were given normal diet for 12 weeks.High fat diet(HFD)group:C57BL/6 mice(n=6)and FXR-/-mice(n=6)were given 45%high fat diet for 12 weeks.After the mice were sacrificed,serum total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDL-C),high density lipoprotein cholesterol(HDL-C),alanine aminotransferase(ALT),aspartate aminotransferase(AST)and total bile acid(TBA)indicators were detected by automatic biochemical analyzer.The expression levels of liver inflammatory genes TNF-α,TLR4 and the downstream genes of FXR small heterodimer partner(SHP),cholesterol 7α-hydroxylase(CYP7A1)were determined by RT-PCR.Liver steatosis was observed by HE staining.Result There was no difference in body weight between C57BL/6 mice and FXR-/-mice under high fat diet,but FXR-/-mice showed more severe glucose tolerance than C57BL/6 mice(P<0.01),lipid metabolism disorder(P<0.01),serum bile acid increase(P<0.01),liver inflammation(P<0.01)and hepatic steatosis.Conclusion Deletion of FXR caused disorders of glucose and lipid metabolism,abnormal bile acid metabolism and hepatic steatosisin mice,but that required induction of high fat diet.