Dimethyl fumarate attenuates cholestatic liver injury by activating the NRF2 and FXR pathways and suppressing NLRP3/GSDMD signaling in mice

Ziqian Xu; Wan Tang; Qiaoling Xie; Xinyu Cao; Mengni Zhang; Xiaoxun Zhang; Jin Chai

doi:10.1016/j.yexcr.2023.113781

Dimethyl fumarate attenuates cholestatic liver injury by activating the NRF2 and FXR pathways and suppressing NLRP3/GSDMD signaling in mice

Exp Cell Res. 2023 Nov 15;432(2):113781. doi: 10.1016/j.yexcr.2023.113781. Epub 2023 Sep 16.

Authors

Ziqian Xu¹, Wan Tang², Qiaoling Xie², Xinyu Cao², Mengni Zhang², Xiaoxun Zhang³, Jin Chai⁴

Affiliations

¹ School of Medicine, Chongqing University, Chongqing 400030, China; Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing 400038, China.
² Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing 400038, China.
³ Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing 400038, China. Electronic address: xiaoxun.zhang@cldcsw.org.
⁴ School of Medicine, Chongqing University, Chongqing 400030, China; Department of Gastroenterology, Institute of Digestive Diseases of PLA, Cholestatic Liver Diseases Center, and Center for Metabolic Associated Fatty Liver Disease, The First Affiliated Hospital (Southwest Hospital) to Third Military Medical University (Army Medical University), Chongqing 400038, China; The Second Affiliated Hospital, University of South China, Hengyang 421001, China. Electronic address: jin.chai@cldcsw.org.

PMID: 37722551
DOI: 10.1016/j.yexcr.2023.113781

Abstract

The progression of cholestasis is characterized by excessive accumulation of bile acids (BAs) in the liver, which leads to oxidative stress (OS), inflammation and liver injury. There are currently limited treatments for cholestasis. Therefore, appropriate drugs for cholestasis treatment need to be developed. Dimethyl fumarate (DMF) has been widely used in the treatment of various diseases and exerts antioxidant and anti-inflammatory effects, but its effect on cholestatic liver disease remains unclarified. We fed mice 3,5-diethoxycarbonyl-1,4-dihydrocollidine or cholic acid to induce cholestatic liver injury and treated these mice with DMF to evaluate its protective ability. Alanine aminotransferase, aspartate aminotransferase, and total liver BAs were assessed as indicators of liver function. The levels of OS, liver inflammation, transporters and metabolic enzymes were also measured. DMF markedly altered the relative ALT and AST levels and enhanced the liver antioxidant capacity. DMF regulated the MST/NRF2 signaling pathway to protect against OS and reduced liver inflammation through the NLRP3/GSDMD signaling pathway. DMF also regulated the levels of BA transporters by promoting FXR protein expression. These findings provide new strategies for the treatment of cholestatic liver disorders.

Keywords: Cholestasis; Dimethyl fumarate; FXR; Liver injury; NRF2.