Suchergebnisse

Nonalcoholic fatty liver disease (NAFLD), ranging from nonalcoholic fatty liver to nonalcoholic 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, using conditional liver‐specific Dusp9‐knockout (Dusp9‐CKO) mice and Dusp9‐transgenic mice, we showed that Dusp9 was a key suppressor of high‐fat diet–induced hepatic steatosis and inflammatory responses and that Dusp9 deficiency aggravated high‐fat high‐cholesterol diet–induced liver fibrosis. Dusp9 was shown to exert its effects by blocking apoptosis signal–regulating kinase 1 (ASK1) phosphorylation and the subsequent activation of p38 and c‐Jun NH2‐terminal kinase signaling. Conclusion: Hepatocyte Dusp9 prevents NAFLD and NASH progression in mice, including lipid accumulation, glucose metabolism disorders, and 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.

Nonalcoholic fatty liver disease (NAFLD), which has a wide global distribution, includes different stages ranging from simple steatosis to nonalcoholic steatohepatitis, advanced fibrosis, and liver cirrhosis according to the degree of severity. Chronic low‐grade inflammation, insulin resistance, and lipid accumulation are the leading causes of NAFLD. To date, no effective medicine for NAFLD has been approved by governmental agencies. Our study demonstrated that the expression of dual‐specificity phosphatase 26 (Dusp26), a member of the Dusp protein family, was decreased in the liver tissue of mice with hepatic steatosis and genetically obese (ob/ob) mice. In our study, hepatic steatosis, inflammatory responses, and insulin resistance were exacerbated in liver‐specific Dusp26‐knockout (KO) mice but ameliorated in liver‐specific Dusp26‐transgenic mice induced by a high‐fat diet. In addition, the degree of liver fibrosis was aggravated in high‐fat high‐cholesterol diet–induced Dusp26‐KO mice. We further found that the binding of Dusp26 to transforming growth factor beta–activated kinase 1 (TAK1) to block the phosphorylation of TAK1 regulated the TAK1–p38/c‐Jun NH2‐terminal kinase signaling axis to alleviate hepatic steatosis and metabolic disturbance. Conclusion: These findings suggest that Dusp26 is a good TAK1‐dependent therapeutic target for NAFLD.