Dual‐specificity Phosphatase 26 Protects Against Nonalcoholic Fatty Liver Disease in Mice through TAK1 Suppression

Abstract

Nonalcoholic fatty liver disease (NAFLD), which has a wide global distribution, includes different stages ranging from simple steatosis to, nonalcoholic steatohepatitis (NASH), 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 observed that the expression of Dusp26 (dual‐specificity phosphatase 26), 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 (HFD). In addition, the degree of liver fibrosis was aggravated in high‐fat high‐cholesterol diet (HFHC)‐induced Dusp26‐KO mice. We further found that the binding of Dusp26 to TAK1 to block the phosphorylation of TAK1 regulated the TAK1‐p38/JNK signaling axis to alleviate hepatic steatosis and metabolic disturbance. Conclusions

These findings suggest that Dusp26 is a good TAK1‐dependent therapeutic target for NAFLD.

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