Allocholic acid protects against α‐naphthylisothiocyanate‐induced cholestasis in mice by ameliorating disordered bile acid homeostasis

Author:

Han Xue1,Lin Chuyi1,Liu Huijie1,Li Shan1,Hu Bei2,Zhang Lei1ORCID

Affiliation:

1. MOE International Joint Research Laboratory on Synthetic Biology and Medicines, School of Biology and Biological Engineering South China University of Technology Guangzhou China

2. Department of Emergency Medicine, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou China

Abstract

AbstractCholestasis is a pathological condition characterized by disruptions in bile flow, leading to the accumulation of bile acids (BAs) in hepatocytes. Allocholic acid (ACA), a unique fetal BA known for its potent choleretic effects, reappears during liver regeneration and carcinogenesis. In this research, we investigated the protective effects and underlying mechanisms of ACA against mice with cholestasis brought on by α‐naphthylisothiocyanate (ANIT). To achieve this, we combined network pharmacology, targeted BA metabolomics, and molecular biology approaches. The results demonstrated that ACA treatment effectively reduced levels of serum AST, ALP, and DBIL, and ameliorated the pathological injury caused by cholestasis. Network pharmacology analysis suggested that ACA primarily regulated BA and salt transport, along with the signaling pathway associated with bile secretion, to improve cholestasis. Subsequently, we examined changes in BA metabolism using UPLC‐MS/MS. The findings indicated that ACA pretreatment induced alterations in the size, distribution, and composition of the liver BA pool. Specifically, it reduced the excessive accumulation of BAs, especially cholic acid (CA), taurocholic acid (TCA), and β‐muricholic acid (β‐MCA), facilitating the restoration of BA homeostasis. Furthermore, ACA pretreatment significantly downregulated the expression of hepatic BA synthase Cyp8b1, while enhancing the expression of hepatic efflux transporter Mrp4, as well as the renal efflux transporters Mdr1 and Mrp2. These changes collectively contributed to improved BA efflux from the liver and enhanced renal elimination of BAs. In conclusion, ACA demonstrated its potential to ameliorate ANIT‐induced liver damage by inhibiting BA synthesis and promoting both BA efflux and renal elimination pathways, thus, restoring BA homeostasis.

Funder

National Basic Research Program of China

Publisher

Wiley

Subject

Toxicology

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