Obeticholic Acid Protects Against Cholestatic Liver Injury Induced by Lithocholic Acid via Inhibiting Exogenous Cell Apoptosis

Abstract Background: Lithocholic acid (LCA) is one kind of endogenous bile acids which is a typical index in primary biliary cholangitis (PBC). It could cause severe cholestatic liver injury in rodents. Obeticholic acid (OCA) is a major treatment for PBC. However, its effect and mechanism in LCA-induced liver injury was still unclear beside of bile acid regulation. This study aims to evaluate the hepatoprotective effect and mechanism of OCA against LCA-induced cholestatic liver injury. Results: LCA-induced upregulations of ALT, AST, ALP and TBA were reduced and the bile acid profiles in serum, liver and bile were improved significantly by OCA. This bile acid regulating effect of OCA was mainly based on increasing the expression of bile acid efflux transporters bile salt export pump (BSEP), multidrug resistant associated protein 2 (MRP2), MRP3 and multi-drug resistance 3 (MDR3) instead of bile acid synthesis inhibition. Furthermore, it was found that OCA reduced the activation and expression of Caspase 8/3 signaling pathway without the change of p-MLKL and BAX in LCA-induced cholestatic model. And the inhibition of Caspase 8/3 signaling pathway depended on the activation of Farnesoid X receptor (FXR) to inhibit Caspase 8 cleavage to form a active complex.Conclusions: This study found OCA improved LCA-induced cholestatic liver injury via FXR-induced exogenous cell apoptosis, which provided a new evidence for the application of OCA to ameliorate PBC in clinical.

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Mast Cell Signaling Regulates Biliary Farnesoid X Receptor and Apical Sodium Bile Acid Transporter Expression During Cholestatic Liver Injury

The FASEB Journal ◽

10.1096/fasebj.2020.34.s1.02044 ◽

2020 ◽

Vol 34 (S1) ◽

pp. 1-1

Author(s):

Vik Meadows ◽

Lindsey Kennedy ◽

Heather Francis

Keyword(s):

Mast Cell ◽

Bile Acid ◽

Liver Injury ◽

Cell Signaling ◽

Farnesoid X Receptor ◽

Bile Acid Transporter ◽

Acid Transporter ◽

Cholestatic Liver Injury ◽

Transporter Expression

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.758632 ◽

2021 ◽

Vol 9 ◽

Author(s):

Peijie Wu ◽

Ling Qiao ◽

Han Yu ◽

Hui Ming ◽

Chao Liu ◽

...

Keyword(s):

Bile Acid ◽

Liver Injury ◽

Protective Effect ◽

Bile Acids ◽

Liver Toxicity ◽

Enterohepatic Circulation ◽

Receptor Activation ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Cholestatic Diseases

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.

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