Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress

Zhe Zhang, Xiang Kai Leng, Yuan Yuan Zhai, Xiao Zhang, Zhi Wei Sun, Jun Ying Xiao, Jun Feng Lu, Kun Liu, Bo Xia, Qi Gao, Miao Jia, Cheng Qi Xu, Yi Na Jiang, Xiao Gang Zhang (), Kai Shan Tao () and Jiang Wei Wu ()
Additional contact information
Zhe Zhang: College of Animal Science and Technology, Northwest A&F University
Xiang Kai Leng: College of Animal Science and Technology, Northwest A&F University
Yuan Yuan Zhai: College of Animal Science and Technology, Northwest A&F University
Xiao Zhang: College of Animal Science and Technology, Northwest A&F University
Zhi Wei Sun: Beijing Sungen Biomedical Technology Co. Ltd
Jun Ying Xiao: College of Animal Science and Technology, Northwest A&F University
Jun Feng Lu: College of Animal Science and Technology, Northwest A&F University
Kun Liu: Xi-Jing Hospital, Air Force Medical University
Bo Xia: College of Animal Science and Technology, Northwest A&F University
Qi Gao: Beijing Sungen Biomedical Technology Co. Ltd
Miao Jia: Beijing Sungen Biomedical Technology Co. Ltd
Cheng Qi Xu: Huazhong University of Science and Technology
Yi Na Jiang: the First Affiliated Hospital of Xi’an Jiaotong University
Xiao Gang Zhang: the First Affiliated Hospital of Xi’an Jiaotong University
Kai Shan Tao: Xi-Jing Hospital, Air Force Medical University
Jiang Wei Wu: College of Animal Science and Technology, Northwest A&F University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.

Date: 2024
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DOI: 10.1038/s41467-024-46135-9

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