GLT25D2 Is Critical for Inflammatory Immune Response to Promote Acetaminophen-Induced Hepatotoxicity by Autophagy Pathway

Xiaohui Zhang; Lele Guo; Xiangying Zhang; Ling Xu; Yuan Tian; Zihao Fan; Hongshan Wei; Jing Zhang; Feng Ren

doi:10.3389/fphar.2020.01187

GLT25D2 Is Critical for Inflammatory Immune Response to Promote Acetaminophen-Induced Hepatotoxicity by Autophagy Pathway

Front Pharmacol. 2020 Sep 18:11:01187. doi: 10.3389/fphar.2020.01187. eCollection 2020.

Authors

Xiaohui Zhang¹, Lele Guo¹, Xiangying Zhang², Ling Xu², Yuan Tian², Zihao Fan², Hongshan Wei³, Jing Zhang¹, Feng Ren²

Affiliations

¹ Department of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China.
² Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China.
³ Department of Gastroenterology, Beijing Ditan Hospital, Capital Medical University, Beijing, China.

Abstract

Acetaminophen (APAP) overdose induces hepatocyte necrosis and causes liver hepatotoxicity. Currently, the role of galactosyltransferase in APAP-induced liver injury is still unclear. This study assessed the contribution of the GLT25D2 gene, a kind of collagen galactosyltransferase, to the development of APAP-induced liver injury. This study found that the expression of GLT25D2 markedly increased first and then decreased in the liver of mice treated with APAP, however, it downregulated in the liver of APAP overdose-patients compared with normal controls. Knockout of GLT25D2 significantly ameliorated the liver injury, meanwhile, it downregulated the proinflammatory cytokines (IL-6, TNF-α) and chemokines (CXCL-10, MIG and CXCL-1) levels, however, and upregulated the anti-inflammatory cytokines (IL-22, IL-10) levels. Mechanistic explorations showed that (1) GLT25D2 knockout promoted autophagy pathway; and (2) the GLT25D2 knockout-induced autophagy selected to clear damaged mitochondria in APAP-induced liver injury by mitophagy; and (3) the autophagy intervention by Atg 7 siRNA cancelled liver protection by knockout of GLT25D2 through regulating liver inflammation. In conclusion, our study proves that the upregulated expression of GLT25D2 decreased autophagy contributing to APAP-induced hepatotoxicity by mediating the inflammatory immune regulatory mechanism.

Keywords: GLT25D2; acetaminophen; acute liver injury; autophagy; liver inflammation.