Dual‐Specificity Phosphatase 26 Protects Against Nonalcoholic Fatty Liver Disease in Mice Through Transforming Growth Factor Beta–Activated Kinase 1 Suppression

Abstract

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.

Modeling alcoholic liver disease in a human Liver-Chip

“…4C) ( Fig. 3g) andaltered the expression of DUSP1 71 (Fig. 3g), in further support of the stress response induced by ethanol in the liver chip.…”

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

“…A more recent study showed that DUSP12, which plays an important role in brown adipocyte differentiation, physically binds to ASK1, promotes its dephosphorylation, and inhibits its action on p38α/β in order to reducelipogenesis and to suppress lipid accumulation in livers of high-fat fed mice [167]. Similar to DUSP12, DUSP14, DUSP26 and MKP-5 suppress the development of hepatic steatosis by inhibiting p38s [167][168][169][170]. Both DUSP14 and DUSP26 directly bind and dephosphorylate TAK1 kinase, which results in the inhibition of TAK1 and its downstream targets JNKs and p38s [168,169].…”

“…Similar to DUSP12, DUSP14, DUSP26 and MKP-5 suppress the development of hepatic steatosis by inhibiting p38s [167][168][169][170]. Both DUSP14 and DUSP26 directly bind and dephosphorylate TAK1 kinase, which results in the inhibition of TAK1 and its downstream targets JNKs and p38s [168,169]. MKP-5 prevents the development of hepatic steatosis by suppressing p38-ATF2 and p38-PPARγ signaling axis to reduce hepatic lipid accumulation [170].…”

Emerging medical therapies for non-alcoholic fatty liver disease and for alcoholic hepatitis

“…ASK1 is upregulated in NASH patients and correlates with the fibrosis stage. In animal models, inhibition of ASK1 as well as molecules upstream and downstream of the pathway improved NASH and hepatic lipid metabolism (36,37). Despite encouraging results from a small phase 2 study (38), selonsertib failed to improve NASH or fibrosis in the phase 3 STELLAR Study (https:// www.gilead.com/news-and-press/press-room/pressreleases/2019/4/gilead-announces-topline-data-fromphase-3-stellar3-study-of-selonsertib-in-bridging-fibrosis-f3-due-to-nonalcoholic-steatohepatitis-nash, accessed on 25 April 2019).…”