Arbutin Alleviates the Liver Injury of α-Naphthylisothiocyanate-induced Cholestasis Through Farnesoid X Receptor Activation.

Peijie Wu,Chao Liu,Han Yu,Baixue Li,Wenjun Wu,Ling Qiao,Hui Ming

doi:10.3389/fcell.2021.758632

Abstract

Cholestasis is a kind of stressful syndrome along with liver toxicity, which has been demonstrated to be related to fibrosis, cirrhosis, even cholangiocellular or hepatocellular carcinomas. Cholestasis usually caused by the dysregulated metabolism of bile acids that possess high cellular toxicity and synthesized by cholesterol in the liver to undergo enterohepatic circulation. In cholestasis, the accumulation of bile acids in the liver causes biliary and hepatocyte injury, oxidative stress, and inflammation. The farnesoid X receptor (FXR) is regarded as a bile acid–activated receptor that regulates a network of genes involved in bile acid metabolism, providing a new therapeutic target to treat cholestatic diseases. Arbutin is a glycosylated hydroquinone isolated from medicinal plants in the genus Arctostaphylos, which has a variety of potentially pharmacological properties, such as anti-inflammatory, antihyperlipidemic, antiviral, antihyperglycemic, and antioxidant activity. However, the mechanistic contributions of arbutin to alleviate liver injury of cholestasis, especially its role on bile acid homeostasis via nuclear receptors, have not been fully elucidated. In this study, we demonstrate that arbutin has a protective effect on α-naphthylisothiocyanate–induced cholestasis via upregulation of the levels of FXR and downstream enzymes associated with bile acid homeostasis such as Bsep, Ntcp, and Sult2a1, as well as Ugt1a1. Furthermore, the regulation of these functional proteins related to bile acid homeostasis by arbutin could be alleviated by FXR silencing in L-02 cells. In conclusion, a protective effect could be supported by arbutin to alleviate ANIT-induced cholestatic liver toxicity, which was partly through the FXR pathway, suggesting arbutin may be a potential chemical molecule for the cholestatic disease.

Highlights

Cholestasis, a kind of stressful syndrome induced by hormones, drugs, cytokines, or progressive bile duct destruction or stones, increases the probability of hepatitis, cirrhosis, liver cancer, or other gallbladder and hepatic diseases due to the excessive accumulation of toxic biliary components like cholesterol, bilirubin, and bile acids (BAs) in the liver and blood (Zollner and Trauner, 2006; Li et al, 2016)
The results did not show enhanced cytotoxicity monitored via lactate dehydrogenase (LDH) assay (Figure 1D) the serum levels of AST and ALT did not change significantly in mice treated with arbutin 40 mg/kg, implicating that arbutin did not exert significant cytotoxicity in vitro and in vivo
To further validate whether arbutin could be a potential agonist for farnesoid X receptor (FXR), we transfected with siRNA to knockdown the FXR in L-02 cells; we analyzed the levels of the FXR by Western blot and fluorescence absorbance (Figures 5D,E). These results indicated that the FXR might have participated in arbutin regulated genes involved in BAs metabolism, suggesting arbutin may be a potential and efficient agonist for FXR to exert the hepatoprotection against cholestasis caused by administered α-naphthylisothiocyanate (ANIT)

Summary

Introduction

Cholestasis, a kind of stressful syndrome induced by hormones, drugs, cytokines, or progressive bile duct destruction or stones, increases the probability of hepatitis, cirrhosis, liver cancer, or other gallbladder and hepatic diseases due to the excessive accumulation of toxic biliary components like cholesterol, bilirubin, and bile acids (BAs) in the liver and blood (Zollner and Trauner, 2006; Li et al, 2016). Recent studies reported that the incidence of liver cancer, biliary tract cancer, and several other gastrointestinal tumors is increased when the homeostasis of bile acids metabolism is disrupted (Navaneethan et al, 2021; Ocvirk and O’Keefe, 2021; Rimland et al, 2021; Wu et al, 2021). Proper recuperation of bile acids is paramount for cholestasis therapy and prevention

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Results

Conclusion