CFTR抑制ApoE^(-/-)鼠高同型半胱氨酸血症诱导的肝损伤

CFTR suppressing hyperhomocysteinemia-induced hepatocyte damage in ApoE^(-/-) mice

目的:探讨囊性纤维化跨膜转导调节因子(CFTR)在高同型半胱氨酸血症(HHcy)致ApoE^(-/-)鼠肝损伤中的作用。方法:5周龄雄性ApoE^(-/-)鼠36只随机分为模型对照组、模型组和治疗组,分别给予普通、高蛋氨酸、高蛋氨酸加叶酸饮食,C57BL/6J雄鼠12只,普通饮食,为正常对照组。检测小鼠血清Hcy、ALT和AST变化,Hcy(100μmol/L)及100 Hcy+F(100μmol/L Hcy+叶酸)干预肝细胞后,检测肝组织和细胞内CFTR m RNA和蛋白水平,分析CFTR激动剂(VX-770)与抑制剂[CFTR(inh)-17]干预细胞后对CFTR表达及ALT和AST含量的影响。结果:模型组ApoE^(-/-)鼠血清Hcy、ALT和AST显著升高,CFTR表达下降(P<0.05),而治疗组可拮抗Hcy、ALT、AST、CFTR的改变(P<0.05);Hcy(100μmol/L)引起肝细胞CFTR表达降低而ALT和AST升高(P<0.05),叶酸对这一改变起缓解作用。VX-770和CFTR(inh)-17干预后可改变肝细胞内ALT和AST含量。结论 :CFTR通过调控ALT和AST抑制HHcy致肝细胞损伤过程。

Objective To investigate the function of CFTR in ApoE^-/- mice with HHcy-induced hepatocellular injury. Methods Thirty six 5-week old ApoE^-/- mice were divided into three groups, including the ApoE^-/- group, the HHcy group and the intervention group,（n = 12）. Twelve normal C57 BL / 6J mice were fed with regular mouse diet as the normal control（SPF grade）. HL-7702 human liver cells were intervened by Hcy（100 μmol / L） and 100 μmol / L Hcy ＋ folic acid（100 μmol / L Hcy ＋ F）. The changes of Hcy, ALT and AST in the serum and the expression of CFTR m RNA and protein in liver and liver cells were detected. The concentrations of ALT and AST in the liver cell intervened by VX-770 agonist and CFTR（inh）-172 inhibitor were measured by ELISA. Results Compared with the control group, the levels of Hcy, ALT and AST were higher and the levels of CFTR m RNA and protein were lower in the Meth group（P〈0.05）, while the reverse result in the Meth ＋ F group（P〈0.05）. Compared with the control group, the levels of CFTR m RNA and protein were decreased and the levels of ALT and AST were increased in the 100 μmol / L Hcy group（P〈0.05）. Compared with the 100 μmol / L Hcy group, the levels of CFTR m RNA and protein were increased and the levels of ALT and AST were decreased in the 100 μmol / L Hcy ＋ F group（P〈0.05）. Stimulated with VX-770 can reduce the concentrations of ALT and AST and the vice versa in the CFTR（inh）-17 group the concentration was increased in liver cells. Conclusion CFTR plays an important role in the regulation of hepatocellular injury by HHcy.