Article

18β-Glycyrrhetinic acid protects against alphanaphthylisothiocyanate- induced cholestasis through activation of the Sirt1/FXR signaling pathway

Authors: Shou-yan Wu1,2, Shi-chao Cui2,3, Le Wang1,2, Yi-ting Zhang1,2, Xiao-xia Yan1,2, Heng-lei Lu1,2, Guo-zhen Xing1,2, Jin Ren1,2, Li-kun Gong1,2
1 Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China
2 University of Chinese Academy of Sciences, 100049 Beijing, China
3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203 Shanghai, China
Correspondence to: Li-kun Gong: lkgong@cdser.simm.ac.cn,
DOI: 10.1038/s41401-018-0110-y
Received: 23 March 2018
Accepted: 8 July 2018
Advance online: 30 July 2018

Abstract

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.
Keywords: hepatoprotective effect; cholestatic liver injury; 18β-glycyrrhetinic acid (18b-GA); FXR; Sirt1; bile acid transporters

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