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Open Access 03-01-2024 | Original Article

Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation

Authors: Shu Feng, Xingming Xie, Jianchao Li, Xu Xu, Chaochun Chen, Gaoliang Zou, Guoyuan Lin, Tao Huang, Ruihan Hu, Tao Ran, Lu Han, Qingxiu Zhang, Yuanqingxiao Li, Xueke Zhao

Published in: Hepatology International | Issue 3/2024

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Abstract

Background

Altered patterns of bile acids (BAs) are frequently present in liver fibrosis, and BAs function as signaling molecules to initiate inflammatory responses. Therefore, this study was conducted to uncover the notably altered components of BAs and to explore the pathway of altered BA induced inflammation in the development of liver fibrosis.

Methods

Bile acids were quantified by ultraperformance liquid chromatography coupled to mass spectrometry (UPLC‒MS/MS). Cell Counting Kit-8 assays were used to determine the proliferative capacity of HSCs. Transwell assays and wound healing assays were used to determine the migratory capacity of LX2 cells. Protein expression was evaluated by western blotting.

Results

Plasma bile acid analysis showed higher levels of GCDCA, TCDCA, GCA and TCA in patients with liver fibrosis than in normal controls. The AUC of GCDCA was the highest. Western blotting showed that GCDCA treatment increased the expression of NLRP3-related proteins and collagen1 in vitro and significantly increased LX2 cells proliferation and migration. Furthermore, knockdown of NLRP3 or overexpression of FXR in LX2 cells decreased the expression of the above proteins, and FXR inhibited NLRP3 (ser 295) phosphorylation in vitro and vivo. In vivo, HE, Masson’s trichrome, and Sirius Red staining showed that GCDCA increased collagen fibers in the mouse liver, and the expression of NLRP3-related proteins, collagen 1, and α-SMA in the liver increased significantly. However, the knockout of NLRP3 reversed these patterns.

Conclusion

(1) Primary conjugated bile acids increased in patients with liver fibrosis; (2) GCDCA induce hepatic fibrosis via the NLRP3 inflammasome pathway; (3) FXR inhibits NLRP3 activity by restraining its phosphorylation; (4) knockdown or knockout of NLRP3 may relieve the onset of hepatic fibrosis.
Appendix
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Literature
16.
go back to reference China medical association infectious diseases and parasitic diseases branch, Society of Hepatology. Prevention and treatment scheme of viral hepatitis. Chinese J Hepatol. 2000;8(06):324–329. China medical association infectious diseases and parasitic diseases branch, Society of Hepatology. Prevention and treatment scheme of viral hepatitis. Chinese J Hepatol. 2000;8(06):324–329.
Metadata
Title
Bile acids induce liver fibrosis through the NLRP3 inflammasome pathway and the mechanism of FXR inhibition of NLRP3 activation
Authors
Shu Feng
Xingming Xie
Jianchao Li
Xu Xu
Chaochun Chen
Gaoliang Zou
Guoyuan Lin
Tao Huang
Ruihan Hu
Tao Ran
Lu Han
Qingxiu Zhang
Yuanqingxiao Li
Xueke Zhao
Publication date
03-01-2024
Publisher
Springer India
Published in
Hepatology International / Issue 3/2024
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-023-10610-0

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