Dual-specificity Phosphatase 9 Protects Against Non-alcoholic Fatty Liver Disease in Mice Via ASK 1 Suppression

Non-alcoholic fatty liver disease (NAFLD), ranging from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), is the leading cause of chronic liver diseases. Until now, no medications for NAFLD have been approved by relevant governmental agencies. Dual-specificity phosphatase 9 (Dusp9) is a member of the DUSP protein family. Dusp9 is expressed in insulin-sensitive tissues, and its expression may be modified with the development of insulin resistance (IR). However, the molecular targets and mechanisms of Dusp9 action on NAFLD and NASH remain poorly understood. In this study, by utilizing conditional liver-specific Dusp9-knockout (Dusp9-CKO) mice and Dusp9-transgenic A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. (Dusp9-TG) mice, we showed that Dusp9 was a key suppressor of HFD-induced hepatic steatosis and inflammatory responses and that Dusp9 deficiency aggravated HFHC-induced liver fibrosis. Dusp9 was shown to exert its effects by blocking ASK1 phosphorylation and the subsequent activation of p38 and JNK signaling. In conclusion, hepatocyte Dusp9 prevents NAFL and NASH progression in mice, including lipid accumulation, glucose metabolism disorders, enhanced inflammation and liver fibrosis, in an ASK1-dependent manner. These findings suggest that Dusp9 may be a promising therapeutic target for the treatment of NAFLD and NASH.