Sphingosine 1-phosphate receptor-1 specific agonist SEW2871 ameliorates ANIT-induced dysregulation of bile acid homeostasis in mice plasma and liver

法尼甾体X受体 内科学 受体 孕烷X受体 肝X受体 药理学 G蛋白偶联胆汁酸受体
作者
Tingting Yang,Xue Wang,Zihang Yuan,Yingying Miao,Ziteng Wu,Yuanyuan Chai,Qiongna Yu,Haiyan Wang,Lixin Sun,Xin Huang,Luyong Zhang,Zhenzhou Jiang
出处
期刊:Toxicology Letters [Elsevier]
卷期号:331: 242-253 被引量:5
标识
DOI:10.1016/j.toxlet.2020.06.018
摘要

Dysregulated bile acid (BA) homeostasis is an extremely significant pathological phenomenon of intrahepatic cholestasis, and the accumulated BA could further trigger hepatocyte injury. Here, we showed that the expression of sphingosine-1-phosphate receptor 1 (S1PR1) was down-regulated by α-naphthylisothiocyanate (ANIT) in vivo and in vitro. The up-regulated S1PR1 induced by SEW2871 (a specific agonist of S1PR1) could improve ANIT-induced deficiency of hepatocyte tight junctions (TJs), cholestatic liver injury and the disrupted BA homeostasis in mice. BA metabolic profiles showed that SEW2871 not only reversed the disruption of plasma BA homeostasis, but also alleviated BA accumulation in the liver of ANIT-treated mice. Further quantitative analysis of 19 BAs showed that ANIT increased almost all BAs in mice plasma and liver, all of which were restored by SEW2871. Our data demonstrated that the top performing BAs were taurine conjugated bile acids (T-), especially taurocholic acid (TCA). Molecular mechanism studies indicated that BA transporters, synthetase, and BAs nuclear receptors (NRs) might be the important factors that maintained BA homeostasis by SEW2871 in ANIT-induced cholestasis. In conclusion, these results demonstrated that S1PR1 selective agonists might be the novel and potential effective agents for the treatment of intrahepatic cholestasis by recovering dysregulated BA homeostasis.
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