FOXA2改善肝内胆汁淤积伴高脂血症小鼠肝脏功能和血脂水平

FOXA2 improves liver function and blood lipid levels in mice with intrahepatic cholestasis and hyperlipidemia

目的研究叉头框蛋白A2(forkhead box A2,FOXA2)对肝内胆汁淤积伴高脂血症小鼠肝脏功能和血脂水平的调节作用。方法通过饲喂高胆固醇/胆酸饲料(cholic acid diet,CAD)构建小鼠模型,尾静脉高压注射法向小鼠肝脏内转染FOXA2质粒,使肝细胞过表达FOXA2蛋白。全自动血生化分析仪检测小鼠血清转氨酶、甘油三酯、胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇和胆汁酸水平,比色法检测肝脏内胆固醇水平,ELISA法检测肝脏胆汁酸水平。Western blot检测肝脏FOXA2的表达,RT-PCR检测胆汁酸代谢相关基因mRNA表达情况。HE、油红染色观察肝脏组织结构及脂质积累情况。结果随着CAD饲喂时间延长,小鼠体质量不断下降,胆囊明显增大(P<0.01),转氨酶水平升高、血清胆固醇和低密度脂蛋白胆固醇明显升高(P<0.01),肝脏组织结构受损,肝脏胆固醇、胆汁酸水平升高(P<0.01),脂质累积严重。过表达FOXA2可通过调节肝脏胆汁酸代谢基因明显改善CAD饲喂小鼠肝功能和血脂异常,降低肝脏胆汁酸水平(P<0.01)和肝脏脂质积累。结论FOXA2改善肝内胆汁淤积伴高脂血症小鼠肝脏功能和血脂水平。

Aim To study the regulatory effect of FOXA2 on liver function and blood lipid levels in micewith intrahepatic cholestasis and hyperlipidemia.Methods The model was constructed by feeding high cholesterol/cholic acid(CAD),and the FOXA2 plasmid was injected into the liver of mice by tail vein hypertension,so that the hepatocytes overexpressed FOXA2.The automatic blood biochemical analyzer was uses to detect the blood biochemical indicators of the serum,the colorimetric method to detect the cholesterol level in liver,and ELISA method to detect the liver bile acid level.Western blot was used to determine the expression of liver FOXA2,and RT-PCR to assess the mRNA expression of genes related to bile acid metabolism.H&E and oil red staining were employed to observe liver pathology.Results With the extension feeding time of the CAD,the weight of the mice continued to decrease(P<0.01),the gallbladder increased significantly(P<0.01),and the level of transaminase increased,and serum cholesterol and low-density lipoprotein cholesterol(P<0.01)increased significantly.Liver tissue structure was damaged,liver cholesterol was elevated(P<0.01),bile acid level increased(P<0.01),and lipid accumulation was serious.Overexpression of FOXA2 could significantly improve liver function and dyslipidemia in CAD-fed mice by regulating liver bile acid metabolism genes,and reduce liver bile acid levels(P<0.01)and liver lipid accumulation.Conclusions FOXA2 improves liver function and blood lipid levels in mice with intrahepatic cholestasis and hyperlipidemia.