Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice
Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice
复制标题
Alisol B 23-Acetate 通过 Farnesoid X 受体介导的转运蛋白和酶调节对雌激素诱导的胆汁淤积性肝损伤的小鼠的保护作用
DOI：
10.1007/s11095-015-1727-x
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发表时间：
2015-11-01
影响因子：
3.7
通讯作者：
Liu, Kexin
中科院分区：
文献类型：
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作者：
Meng, Qiang;Chen, Xinli;Liu, Kexin
为探讨泽泻醇B 23-乙酸酯（AB 23 A）对17 α-乙炔基甜菜碱（EE）所致小鼠肝毒性和胆汁淤积的保护作用及其与FXR激活的关系，采用C57 BL/6小鼠皮下注射EE建立胆汁淤积性肝损伤模型。使用血清生物标志物、胆汁流量测定和H&E染色来鉴定AB 23 A治疗后胆汁淤积的改善。采用小鼠原代肝细胞培养、基因沉默实验、实时荧光定量PCR和Western blot分析等方法，研究了AB 23 A对EE诱导的小鼠肝损伤的保护作用，结果表明，AB 23 A通过诱导胆汁外排转运蛋白（Bsep和Mrp 2）的表达，抑制肝摄取转运蛋白（Ntcp）的表达，增加胆汁外排，减少胆汁酸的摄取，从而减轻EE诱导的小鼠肝损伤。AB 23 A还通过抑制Cyp 7a 1和Cyp 8b 1来减少胆汁酸合成，并通过诱导Sult 2a 1的基因表达来增加胆汁酸代谢。我们进一步证明，AB 23 A处理小鼠的转运蛋白和酶的变化以及肝脏组织学的改善在体内被FXR拮抗剂guggulsterone消除，在体外被FXR沉默后被消除。AB 23 A对EE诱导的胆汁淤积产生保护作用，这是由于FXR介导的基因调控。
To investigate protective effects of alisol B 23-acetate (AB23A) against hepatotoxity and cholestasis induced by 17 alpha-ethinylestradiol (EE) in association with farnesoid X receptor (FXR) activation in vivo and in vitro.The cholestatic liver injury model was established by subcutaneous injections of EE in C57BL/6 mice. Serum biomarkers, bile flow assay and H&E staining were used to identify the amelioration of cholestasis after AB23A treatment. Mice primary hepatocytes culture, gene silencing experiment, real-time PCR and Western blot assay were used to elucidate the mechanisms underlying AB23A hepatoprotection.AB23A treatment protected against liver injury induced by EE through increasing hepatic efflux and reducing uptake of bile acid via an induction in efflux transporters (Bsep and Mrp2) and an inhibition in hepatic uptake transporter (Ntcp) expression. AB23A also reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrated that the changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo and were abrogated after FXR was silenced in vitro.AB23A produces protective effects against EE-induced cholestasis, due to FXR-mediated gene regulation.