Early indications of ANIT-induced cholestatic liver injury: Alteration of hepatocyte polarization and bile acid homeostasis
Early indications of ANIT-induced cholestatic liver injury: Alteration of hepatocyte polarization and bile acid homeostasis
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ANIT 诱导的胆汁淤积性肝损伤的早期迹象：肝细胞极化和胆汁酸稳态的改变
DOI：
10.1016/j.fct.2017.09.051
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发表时间：
2017
影响因子：
4.3
通讯作者：
Jiang Zhenzhou
中科院分区：
文献类型：
--
作者：
Yang Tingting;Mei Huifang;Xu Dengqiu;Zhou Wang;Zhu Xiaoyu;Sun Lixin;Huang Xin;Wang Xue;Shu Ting;Liu Jia;Ding Jiaxin;Hozeifa M. Hassan;Zhang Luyong;Jiang Zhenzhou
Hepatocyte polarization is essential for biliary secretion, and loss of polarity causes bile secretory failure and hepatotoxicity. Here, we showed that alpha-naphthyl isothiocyanate (ANIT)-induced liver injury was accompanied by the dynamic interruption of bile acid homeostasis in rat plasma, liver and bile, which was characterized by the redistribution of bile acids in plasma and bile and a small range of fluctuations in the liver. Molecular mechanism studies indicated that these factors are dynamically mediated by the disruption of bile acid transporters and hepatic tight junctions. Dynamic changes in tight junction (TJ) permeability were observed by hepatobiliary barrier function assessment. Hepatocyte polarization was disrupted by ANIT before the development of cholestatic hepatotoxicity and alteration of bile acid metabolic profiles, which were assayed by high-performance liquid chromatography-tandem mass spectrometry, further verifying TJ deficiency. S1PR1 activation with SEW2871 reduced ANIT-induced liver injury by reducing the total serum bile acid concentration, liver functional enzyme activity and inflammation. Our data suggest that hepatocyte polarization plays an important role in maintaining bile acid homeostasis before the development of cholestatic hepatotoxicity and that TJs were more prominent in the early stage of cholestasis. S1PR1 may be a potential target for the prevention of drug-induced cholestatic liver injury.
