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Hepatology. 2018 Apr;67(4):1320-1338. doi: 10.1002/hep.29616. Epub 2018 Mar 2.

Hepatocyte DUSP14 maintains metabolic homeostasis and suppresses inflammation in the liver.

Wang S1, Yan ZZ2, Yang X3,4, An S1, Zhang K1, Qi Y1, Zheng J1, Ji YX3,4, Wang PX3,4,5, Fang C3,4, Zhu XY3,4,5, Shen LJ3,4,5, Yan FJ2, Bao R3, Tian S3,4,5, She ZG3,4,5, Tang YD1.

Author information

1
Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
2
College of Life Sciences, Wuhan University, Wuhan, China.
3
The Institute of Model Animals of Wuhan University, Wuhan, China.
4
Medical Research Institute, School of Medicine, Wuhan University, Wuhan, China.
5
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a prevalent and complex disease that confers a high risk of severe liver disorders. Despite such public and clinical health importance, very few effective therapies are currently available for NAFLD. We report a protective function and the underlying mechanism of dual-specificity phosphatase 14 (DUSP14) in NAFLD and related metabolic disorders. Insulin resistance, hepatic lipid accumulation, and concomitant inflammatory responses, key pathological processes involved in NAFLD development, were significantly ameliorated by hepatocyte-specific DUSP14 overexpression (DUSP14-HTG) in high-fat diet (HFD)-induced or genetically obese mouse models. By contrast, specific DUSP14 deficiency in hepatocytes (DUSP14-HKO) aggravated these pathological alterations. We provided mechanistic evidence that DUSP14 directly binds to and dephosphorylates transforming growth factor β-activated kinase 1 (TAK1), resulting in the reduced activation of TAK1 and its downstream signaling molecules c-Jun N-terminal kinase 1 (JNK), p38, and nuclear factor kappa B NF-κB. This effect was further evidenced by the finding that inhibiting TAK1 activity effectively attenuated the deterioration of glucolipid metabolic phenotype in DUSP14-HKO mice challenged by HFD administration. Furthermore, we identified that both the binding domain and the phosphatase activity of DUSP14 are required for its protective role against hepatic steatosis, because interruption of the DUSP14-TAK1 interaction abolished the mitigative effects of DUSP14.

CONCLUSION:

Hepatocyte DUSP14 is required for maintaining hepatic metabolic homeostasis and for suppressing inflammation, a novel function that relies on constraining TAK1 hyperactivation. (Hepatology 2018;67:1320-1338).

PMID:
29077210
DOI:
10.1002/hep.29616
[Indexed for MEDLINE]

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