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 chronic liver diseases. Nonetheless, the genetic predisposing factors leading to its initiation and progression remain largely unknown. Here, we report that asialoglycoprotein receptor 1 is downregulated in patients with cirrhosis and mice with liver injury. ASGR1 dificiency in mice aggravates acute and chronic liver injuries, whereas hepatic oversepression of ASGR1 protects against these injuries. These effects of ASGR1 occur in an ER stress-dependent manner. Mechanistically, ASGR1 deficiency increases circulating levels of GP73, a mediator of ER stress and thus leading to ER stress-dependent liver injuries. We also found cirrhotic patients with decreased ASGR1 expression along with increased circulating GP73 levels and hepatic ER stress. Together, these data demonstrate that ASGR1 deficiency promotes liver injury through activating GP73 mediated ER stress.Targeting the ASGR1-GP73 axis may provide new avenue for the treatment of liver diseases.