UGCG relieves iNKT cell-mediated liver injury by triggering endoplasmic reticulum stress in mice

Abstract Immune-mediated liver injury is associated with excessive activation of invariant natural killer T (iNKT) cells, and the role and regulatory mechanisms of UDP-glucosylceramide glucosyltransferase (UGCG) in iNKT cell-mediated liver injury remain poorly defined. Here, we report UGCG induced endoplasmic reticulum (ER) stress, which is beneficial for hepatocytes to resist injury caused by iNKT cells, thereby improving immune-mediated liver injury outcomes in mice. UGCG levels were elevated in mice treated with concanavalin A, with excessive activation of iNKT cells. However, after UGCG inhibition, liver injury were alleviated along with reduced activation of iNKT cells. Interestingly, hepatocytes showed marked autophagy upon inhibition of UGCG. Mechanistically, inhibition of UGCG caused an increase in glucose-regulated protein 78, LC3B-II/LC3B-I ratio and phosphorylated NF-κB p65, thereby triggering ER stress-mediated autophagy. These findings showed ER stress links UGCG with hepatic autophagy.