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.

中文翻译：

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鞘氨醇 1-磷酸受体-1 特异性激动剂 SEW2871 改善 ANIT 诱导的小鼠血浆和肝脏胆汁酸稳态失调

胆汁酸（BA）稳态失调是肝内胆汁淤积的一种极为显着的病理现象，BA的积累可进一步引发肝细胞损伤。在这里，我们发现 1-磷酸鞘氨醇受体 1 (S1PR1) 的表达在体内和体外被 α-萘基异硫氰酸酯 (ANIT) 下调。SEW2871（S1PR1 的特异性激动剂）诱导的 S1PR1 上调可以改善 ANIT 诱导的肝细胞紧密连接 (TJ) 缺陷、胆汁淤积性肝损伤和小鼠体内 BA 稳态的破坏。BA 代谢谱表明，SEW2871 不仅逆转了血浆 BA 稳态的破坏，而且减轻了 ANIT 治疗小鼠肝脏中 BA 的积累。对 19 种 BAs 的进一步定量分析表明，ANIT 增加了小鼠血浆和肝脏中几乎所有的 BAs，所有这些都被 SEW2871 恢复了。我们的数据表明，表现最好的 BA 是牛磺酸共轭胆汁酸 (T-)，尤其是牛磺胆酸 (TCA)。分子机制研究表明，BA 转运蛋白、合成酶和 BAs 核受体 (NRs) 可能是 SEW2871 在 ANIT 诱导的胆汁淤积中维持 BA 稳态的重要因素。总之，这些结果表明，S1PR1 选择性激动剂可能是通过恢复失调的 BA 稳态来治疗肝内胆汁淤积的新型潜在有效药物。和 BAs 核受体 (NRs) 可能是 SEW2871 在 ANIT 诱导的胆汁淤积中维持 BA 稳态的重要因素。总之，这些结果表明，S1PR1 选择性激动剂可能是通过恢复失调的 BA 稳态来治疗肝内胆汁淤积的新型潜在有效药物。和 BAs 核受体 (NRs) 可能是 SEW2871 在 ANIT 诱导的胆汁淤积中维持 BA 稳态的重要因素。总之，这些结果表明，S1PR1 选择性激动剂可能是通过恢复失调的 BA 稳态来治疗肝内胆汁淤积的新型潜在有效药物。