IRE1α/NOX4 signaling pathway mediates ROS‐dependent activation of hepatic stellate cells in NaAsO2‐induced liver fibrosis

• Published in: Journal of cellular physiology 2021-02, Vol.236 (2), p.1469-1480
• Main Authors: Tao, Ye, Qiu, Tianming, Yao, Xiaofeng, Jiang, Liping, Wang, Ningning, Jiang, Jintong, Jia, Xue, Wei, Sen, Zhang, Jingyuan, Zhu, Yuhan, Tian, Wenyue, Yang, Guang, Liu, Xiaofang, Liu, Shuang, Ding, Yang, Sun, Xiance
• Format: Article
• Language: English
• Subjects: Adenine; Arsenic; Cell activation; Collagen; Deposition; Endoplasmic reticulum; Exposure; Fibrosis; hepatic stellate cells; Ingestion; Inositol; Liver; liver fibrosis; NAD(P)H oxidase; NADPH-diaphorase; Nicotinamide; Nicotinamide adenine dinucleotide; NOX4; NOX4 protein; Oxidation; Oxidative stress; Reactive oxygen species; ROS; Signal transduction; Sodium arsenite; Stellate cells
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.29952

Liver fibrosis is a severe health problem worldwide, and it is characterized by the activation of hepatic stellate cells (HSCs) and excessive deposition of collagen. Prolonged arsenic exposure can induce HSCs activation and liver fibrosis. In the present study, the results showed that chronic NaAsO2 ingestion could result in liver fibrosis and oxidative stress in Sprague–Dawley rats, along with representative collagen deposition and HSCs activation. In addition, the inositol‐requiring enzyme 1α (IRE1α)–endoplasmic reticulum (ER)‐stress pathway was activated, and the activity of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) was upregulated in rat livers. Simultaneously, the excessive production of reactive oxygen species (ROS) could induce HSCs activation, and NOX4 played an important role in generating ROS in vitro. Moreover, ER stress occurred with HSCs activation at the same time under NaAsO2 exposure, and during ER stress, the IRE1α pathway was responsible for NOX4 activation. Therefore, inhibition of IRE1α activation could attenuate the HSCs activation induced by NaAsO2. In conclusion, the present study manifested that inorganic arsenic exposure could activate HSCs through IRE1α/NOX4‐mediated ROS generation. Here, we found that long‐term NaAsO2 ingestion could result in fibrosis and oxidative stress in Sprague–Dawley rat liver in this study. Furthermore, our results suggested that NaAsO2 caused hepatic stellate cells (HSCs) activation by promoting reactive oxygen species (ROS) accumulation, which was mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4). Moreover, the activation of the inositol‐requiring enzyme 1α (IRE1α)–endoplasmic reticulum (ER)‐stress pathway was associated with the NOX4 activity, ROS accumulation, and HSCs activation.