2. Academic Validation
  3. Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress

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

  • Nat Commun. 2024 Mar 8;15(1):1908. doi: 10.1038/s41467-024-46135-9.
Zhe Zhang # 1,  Xiang Kai Leng # 1,  Yuan Yuan Zhai # 1,  Xiao Zhang 1,  Zhi Wei Sun 2,  Jun Ying Xiao 1,  Jun Feng Lu 1,  Kun Liu 3,  Bo Xia 1,  Qi Gao 2,  Miao Jia 2,  Cheng Qi Xu 4,  Yi Na Jiang 5,  Xiao Gang Zhang 6,  Kai Shan Tao 7,  Jiang Wei Wu 8
Affiliations

Affiliations

  • 1 Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China.
  • 2 Beijing Sungen Biomedical Technology Co. Ltd, Beijing, China.
  • 3 Department of Hepatobiliary Surgery, Xi-Jing Hospital, Air Force Medical University, Xi'an, China.
  • 4 College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 6 Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. little_gang17@xjtu.edu.cn.
  • 7 Department of Hepatobiliary Surgery, Xi-Jing Hospital, Air Force Medical University, Xi'an, China. taokaishan0686@163.com.
  • 8 Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China. wujiangwei@nwafu.edu.cn.
  • # Contributed equally.
PMID: 38459023 DOI: 10.1038/s41467-024-46135-9
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.

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