Cholestasis is a common feature of liver injury, which manifests as bile acid excretion and/or enterohepatic circulation disorders. However, very few effective therapies exist for cholestasis. Recently, 18β-Glycyrrhetinic acid (18b-GA), a major metabolic component of glycyrrhizin, which is the main ingredient of licorice, was reported to protect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis. However, its protective mechanism remains unclear. We hypothesized that 18b-GA may stimulate the signaling pathway of bile acid (BA) transportation in hepatocytes, resulting its hepatoprotective effect. According to the results, 18b-GA markedly attenuated ANIT-induced liver injury as indicated the hepatic plasma chemistry index and histopathology examination. In addition, the expression levels of nuclear factors, including Sirt1, FXR and Nrf2, and their target efflux transporters in the liver, which mainly mediate bile acid homeostasis in hepatocytes, significantly increased. Furthermore, we first revealed that 18b-GA treatment significantly activated FXR, and which can be significantly reduced by EX-527 (a potent and selective Sirt1 inhibitor), indicating that 18b-GA activates FXR through Sirt1. Taken together, 18b-GA confers hepatoprotection against ANIT-induced cholestasis by activating FXR through Sirt1, which promotes gene expression of the efflux transporter, and consequently attenuates dysregulation of bile acid homeostasis in hepatocyte compartments.

中文翻译：

---

18β-甘草次酸通过Sirt1 / FXR信号通路的激活来预防由α-萘基异硫氰酸酯诱导的胆汁淤积。

胆汁淤积是肝损伤的常见特征，表现为胆汁酸排泄和/或肠肝循环障碍。但是，很少有有效的胆汁淤积疗法。最近，据报道甘草的主要成分甘草甜素的主要代谢成分18β-甘草次酸（18b-GA）可以抵抗α-萘基异硫氰酸酯（ANIT）诱导的胆汁淤积。但是，其保护机制仍不清楚。我们假设18b-GA可能会刺激胆汁酸（BA）在肝细胞中运输的信号传导途径，从而起到保护肝脏的作用。根据结果​​，如肝血浆化学指标和组织病理学检查所示，18b-GA可显着减轻ANIT诱导的肝损伤。此外，包括Sirt1，FXR和Nrf2在内的核因子的表达水平，其主要介导肝细胞胆汁酸稳态的肝脏靶外排转运蛋白显着增加。此外，我们首先发现18b-GA处理可以显着激活FXR，而EX-527（一种有效的选择性Sirt1抑制剂）可以显着降低FXR，表明18b-GA通过Sirt1可以激活FXR。两者合计，18b-GA通过Sirt1激活FXR，从而赋予了针对ANIT诱导的胆汁淤积的肝保护，这促进了外排转运蛋白的基因表达，并因此减轻了肝细胞区室胆汁酸稳态的失调。并且可以被EX-527（一种有效的选择性Sirt1抑制剂）显着降低，表明18b-GA通过Sirt1激活FXR。两者合计，18b-GA通过Sirt1激活FXR，从而赋予了针对ANIT诱导的胆汁淤积的肝保护，这促进了外排转运蛋白的基因表达，并因此减轻了肝细胞区室胆汁酸稳态的失调。并且可以被EX-527（一种有效的选择性Sirt1抑制剂）显着降低，表明18b-GA通过Sirt1激活FXR。两者合计，18b-GA通过Sirt1激活FXR，从而赋予了针对ANIT诱导的胆汁淤积的肝保护，这促进了外排转运蛋白的基因表达，并因此减轻了肝细胞区室胆汁酸稳态的失调。