Hepatocyte DUSP14 maintains metabolic homeostasis and suppresses inflammation in the liver

Wang, Siyuan; Yan, Zhenzhen; Yang, Xia; An, Shimin; Zhang, Kuo; Yu, Qi; Zheng, Jilin; Ji, Yan‐Xiao; Wang, Pi-Xiao; Fang, Cheng; Zhu, Xueyong; Shen, Lijun; Yan, Feng-Juan; Bao, Rong; Shen, Tian; She, Zhi‐Gang; Tang, Yi-Da

doi:10.1002/hep.29616

Cited by 52 publications

(44 citation statements)

References 47 publications

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“…In the current study, our results showed that HFD feeding resulted in significantly enhanced TAK1 phosphorylation, JNK1 phosphorylation and IRS1 phosphorylation and reduced Akt phosphorylation in liver of rats, which was consistent with previous research (An et al, ; Ji et al, ; P.X. Wang et al, ; S. Wang et al, ; Yan et al, ; Zhao et al, ).…”

Section: Discussionsupporting

confidence: 93%

“…Further research provided mechanistic evidence that hepatic dual‐specificity phosphatases 14 (DUSP14), directly binds to and dephosphorylates TAK1, resulting in reduced TAK1 phosphorylation and its downstream signaling molecules JNK1, thereby improves insulin sensitivity (S. Wang et al, ). Other research revealed that hepatic ubiquitin specific protease 4 (USP4) and ubiquitin specific protease 18 (USP18), which is also known as UBP43 (L.Q.…”

Section: Introductionmentioning

confidence: 99%

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Exercise ameliorates insulin resistance via regulating TGFβ‐activated kinase 1 (TAK1)‐mediated insulin signaling in liver of high‐fat diet‐induced obese rats

Zhang

Wan

et al. 2018

Journal Cellular Physiology

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Exercise is an effective therapy for insulin resistance. However, the underlying mechanism remains to be elucidated. Previous research demonstrated that TGFβ-activated kinase 1 (TAK1)-dependent signaling plays a crucial character in hepatic insulin resistance. Hepatic ubiquitin specific protease 4 (USP4), USP18, and dual-specificity phosphatases 14 (DUSP14) can suppress TAK1 phosphorylation, besides tumor necrosis factor receptorassociated factor 3 (TRAF3) and tripartite motif 8 (TRIM8) promote its phosphorylation.In this study, we tried to verify our hypothesis that exercise improves insulin resistance in high-fat diet (HFD)-induced obese (DIO) rats via regulating the TAK1 dependent signaling and TAK1 regulators in liver. Forty male Sprague-Dawley rats were randomized into four groups (n = 10): standard diet and sedentary as normal control; fed on HFD and DIO-sedentary; fed on HFD and DIO-chronic exercise; and fed on HFD and DIO-acute exercise. HFD feeding resulted in increased body weight, visceral fat mass, serum FFAs and hepatic lipid deposition, but decreased hepatic glycogen content and insulin sensitivity. Moreover, hepatic TRAF3 and TRIM8 protein levels increased, whereas USP4, USP18, and DUSP14 protein levels were decreased under obese status, which resulted in enhanced TAK1 phosphorylation and impaired insulin signaling. Exercise training, containing chronic and acute mode, both ameliorated insulin resistance.Meanwhile, decreased TAK1, c-Jun N-terminal kinase 1 (JNK1), and insulin receptor substrate 1 (IRS1) phosphorylation enhanced Akt phosphorylation in liver. Moreover, exercise enhanced USP4 and DUSP14 protein levels, whereas decreased TRIM8 protein levels in obese rats' liver. These results showed that exercise triggered a crucial modulation in TAK1-dependent signaling and its regulators in obese rats' liver, and distinct improvement in insulin sensitivity, which provide new insights into the mechanism by which physical exercise improves insulin resistance.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Exercise ameliorates insulin resistance via regulating TGFβ‐activated kinase 1 (TAK1)‐mediated insulin signaling in liver of high‐fat diet‐induced obese rats

Zhang

Wan

et al. 2018

Journal Cellular Physiology

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“…These data suggest that an appropriate level of TAK1 is essential for maintaining physiological functions in the liver. By contrast, consistent with our findings, other studies indicated that hyperactivation of TAK1 promoted HFD‐induced hepatosteatosis and TAK1 suppression was protective against the pathogenesis of NAFLD . Congruently, the same phenomenon was reported in the cardiovascular system.…”

Section: Discussionsupporting

confidence: 92%

Ubiquitin‐Specific Protease 4 Is an Endogenous Negative Regulator of Metabolic Dysfunctions in Nonalcoholic Fatty Liver Disease in Mice

et al. 2018

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Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic steatosis, insulin resistance and inflammation, poses a high risk of cardiometabolic disorders. Ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme, is pivotally involved in regulating multiple inflammatory pathways; however, the role of USP4 in NAFLD is unknown. Here we report that USP4 expression was dramatically downregulated in the livers from NAFLD patients and different NAFLD mouse models induced by a high fat diet (HFD) or a genetic deficiency (ob/ob) as well as in palmitate-treated hepatocytes. Hepatocyte-specific USP4 depletion exacerbated hepatic steatosis, insulin resistance and inflammatory response in HFD-induced NAFLD mice. Conversely, hepatic USP4 overexpression notably alleviated the pathological alterations in two different NAFLD models. Mechanistically, hepatocyte USP4 directly bound to and deubiquitinated transforming growth factor-β activated kinase 1 (TAK1), leading to a suppression of the activation of downstream NF-κB and JNK cascades, which in turn reversed the disruption of the IRS-AKT-GSK3β signaling. In addition, USP4-TAK1 interaction and subsequent TAK1 deubiquitination were required for the amelioration of metabolic dysfunctions. Collectively, the present study provides the first evidence that USP4 functions as a pivotal suppressor in NAFLD and related metabolic disorders. This article is protected by copyright. All rights reserved.

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“…It has been shown that DUSP14 expression decreases during diverse inflammatory states (Jianrong et al, 2019;Zhang et al, 2019;Xia et al, 2019), which is thought to promote inflammation and pathology. DUSP14-deficient mice have enhanced susceptibility to experimental autoimmune encephalitis (Yang et al, 2014), aortic banding-induced cardiac hypertrophy and dysfunction (Li et al, 2016), hepatic and cardiac ischemia-reperfusion injury (Wang et al, 2017b;Lin et al, 2018), and high-fat diet-induced hepatic dysfunction (Wang et al, 2018), all of which have been attributed to its role in MAPK regulation. As necroptosis has been shown to be pathogenic in the aforementioned diseases (Galluzzi et al, 2017), it will be of interest to investigate whether the phenotype of Dusp14 À/À mice in disease models can be attributed to excessive necroptosis.…”

Section: Discussionmentioning

confidence: 99%

Post-translational Modification of OTULIN Regulates Ubiquitin Dynamics and Cell Death

Douglas

Saleh

2019

Cell Reports

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Hepatocyte DUSP14 maintains metabolic homeostasis and suppresses inflammation in the liver

Abstract: 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).

Cited by 52 publications

References 47 publications

Exercise ameliorates insulin resistance via regulating TGFβ‐activated kinase 1 (TAK1)‐mediated insulin signaling in liver of high‐fat diet‐induced obese rats

Exercise ameliorates insulin resistance via regulating TGFβ‐activated kinase 1 (TAK1)‐mediated insulin signaling in liver of high‐fat diet‐induced obese rats

Ubiquitin‐Specific Protease 4 Is an Endogenous Negative Regulator of Metabolic Dysfunctions in Nonalcoholic Fatty Liver Disease in Mice

Post-translational Modification of OTULIN Regulates Ubiquitin Dynamics and Cell Death

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