Aldose reductase -mediated HUR ubiquitination enhances exosome release and hepatic fibrosis via ROS/PI3K/AKT pathway.

INTRODUCTION

Liver fibrosis is caused by the activation of hepatic stellate cells due to various reasons. Our previous research has shown that aldose reductase (AR) played an important role in liver ischemia-reperfusion injury and liver regeneration.

OBJECTIVES

Here, we aimed to investigate the role and mechanism of AR in the progression of liver fibrosis induced by various factors.

METHODS

AR expression was detected in liver tissue of fibrosis patients and mouse models. The role and mechanism of AR in fibrosis progression were investigated in AR knockout mice and cell lines.

RESULTS

AR expression was increased in liver from patients with fibrosis and mouse models. The knockout of AR protected against CCL4 or HFD induced liver injury and development of fibrosis. Furthermore, AR promoted ubiquitization degradation of HUR through competitive binding with OTUB1, thereby exacerbating the accumulation of ROS, and ultimately activating PI3K/AKT pathway. The impaired autophagolysosome resulted in the massive release of exosomes, which activated stellate cells by regulating PTP4a1/SMAD3 pathway. The hepatocyte specific recovery of AR in AR knockout mice aggravated ROS damage and fibrosis, while recovery of HUR in wild-type mice reduced ROS damage and fibrosis.

CONCLUSIONS

In conclusion, these findings suggest that AR might be a promising therapeutic target for treating liver fibrosis.