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

Liver injury is the central pathological process that occurs in most types of liver diseases. Nonetheless, the genetic predisposing factors leading to its initiation and progression remain largely unknown. Here, we report that asialoglycoprotein receptor 1 (ASGR1), is downregulated in cirrhotic patients and liver injured mice. ASGR1 deficiency aggravates, whereas its overexpression ameliorates acute and chronic liver injuries in mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum (ER) stress mediator Golgi Protein 73 (GP73) and facilitates its lysosomal degradation. Deficiency of ASGR1 increases circulating levels of GP73, leading to ER stress-induced liver injury, while neutralization of GP73 markedly attenuates these injuries. We also found circulating levels of GP73 and hepatic ER stress were negatively correlated with hepatic ASGR1 expression in cirrhotic patients. These results demonstrate that ASGR1-GP73 axis as a crucial pathway of liver injury. Together, these findings identify ASGR1 as a novel gene underlying genetic predisposition to liver injury and the ASGR1-GP73 axis as a potential therapeutic target for liver injury. Comparative gene expression profiling analysis of RNA-seq data for livers of WT and Asgr1-/- mice .肝损伤是多数肝脏疾病发生发展过程中的核心病理进程。然而，驱动其起始与进展的遗传易感因素仍在很大程度上未被阐明。本研究发现，去唾液酸糖蛋白受体1（asialoglycoprotein receptor 1, ASGR1）在肝硬化患者与肝损伤小鼠体内均呈低表达状态。ASGR1基因缺失会加重小鼠的急性与慢性肝损伤，而过表达ASGR1则可缓解此类损伤。从机制层面分析，ASGR1可与内质网应激（endoplasmic reticulum stress, ER）介质高尔基体蛋白73（Golgi Protein 73, GP73）结合，并促进其经溶酶体途径降解。ASGR1缺失会升高循环中GP73的水平，进而引发内质网应激介导的肝损伤；而中和GP73则可显著减轻此类肝损伤。本研究同时发现，在肝硬化患者体内，循环GP73水平与肝脏内质网应激程度，均与肝脏ASGR1的表达量呈负相关。上述结果证实，ASGR1-GP73信号轴是调控肝损伤的关键通路。综上，本研究明确ASGR1是调控肝损伤遗传易感性的全新基因，且ASGR1-GP73信号轴可作为肝损伤潜在的治疗靶点。本研究对野生型（Wild Type, WT）与Asgr1基因敲除（Asgr1-/-）小鼠的肝脏组织RNA-seq数据进行了比较基因表达谱分析。