Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, China.
Beijing Sungen Biomedical Technology Co. Ltd, Beijing, China.
Nat Commun. 2024 Mar 8;15(1):1908. doi: 10.1038/s41467-024-46135-9.
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.
肝损伤是大多数肝脏疾病的核心病理过程，但导致个体易发生肝损伤起始和进展的遗传因素仍知之甚少。本文中，作者发现，肝脏特异性表达的凝集素去唾液酸糖蛋白受体 1（ASGR1）在肝纤维化或肝硬化患者以及肝损伤的雄性小鼠中表达下调。ASGR1 缺失会加重，而过表达则会减轻对乙酰氨基酚诱导的急性肝损伤和 CCl4 诱导的慢性肝损伤。机制上，ASGR1 与内质网应激介质 GP73 结合，并促进其溶酶体降解。ASGR1 耗竭会增加循环 GP73 水平，并促进 GP73 与 BIP 之间的相互作用，激活内质网应激，导致肝损伤。中和 GP73 不仅可以减轻 ASGR1 缺失引起的肝损伤，还可以提高接受致死剂量对乙酰氨基酚的小鼠的存活率。综上，这些发现确定了 ASGR1 是易发生肝损伤的潜在遗传决定因素，并提出其作为治疗肝损伤的治疗靶点。
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