Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4

Zhao, Guang‐Nian; Zhang, Peng; Gong, Jun; Zhang, Xiaojing; Wang, Pi-Xiao; Yin, Miao; Jiang, Zhou; Shen, Lijun; Ji, Yan‐Xiao; Tong, Jingjing; Wang, Yutao; Wei, Qianqian; Wang, Yong; Zhu, Xueyong; Zhang, Xin; Fang, Jing; Xie, Qingguo; She, Zhi‐Gang; Wang, Zhihua; Huang, Zan; Li, Hongliang

doi:10.1038/nm.4334

Cited by 122 publications

(111 citation statements)

References 75 publications

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“…Insulin resistance and inflammation are vital parts in the development of hepatic steatosis . USP18‐HTG mice exhibited decreased fasting blood glucose and insulin levels in contrast with their control littermates fed HFD (Fig.…”

Section: Resultsmentioning

confidence: 96%

USP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity

Zhao

Shen

et al. 2017

Hepatology

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Section: Resultsmentioning

confidence: 96%

USP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity

Zhao

Shen

et al. 2017

Hepatology

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“…H,J). Previous studies demonstrated that in obese individuals, Iκ kinase β (IKKβ)‐mediated activation of NF‐κB by nutritional overload triggers hepatic inflammatory reaction . We thus further investigated whether USP4 mediated the IKKβ/NF‐κB signaling pathway during HFD‐induced related pathologies.…”

Section: Resultsmentioning

confidence: 99%

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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“…Randomization and blinding strategies were used whenever possible. Animal cohort sizes were determined on the basis of similar previous studies …”

Section: Methodsmentioning

confidence: 99%

Caspase Recruitment Domain Protein 6 Protects Against Hepatic Steatosis and Insulin Resistance by Suppressing Apoptosis Signal–Regulating Kinase 1

Sun

Zeng²,

Cheng

et al. 2018

Hepatology

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The rapidly increasing prevalence of metabolic disorders associated with nonalcoholic fatty liver disease (NAFLD) warrants further study of the underlying mechanisms to identify key regulators as targets for the development of therapeutic interventions. Caspase recruitment domain protein 6 (Card6), as a member of the CARD family that regulates cell death and immunity, may potentially control this process. Indeed, Card6 down-regulation was found to be closely associated with the fatty livers observed in NAFLD patients, obese mice, and a palmitate-treated hepatocyte model. Gain-of-function and loss-of-function Card6 mouse models demonstrated that Card6 protected mice from insulin resistance, hepatic steatosis, and inflammatory responses upon high-fat diet administration. Mechanistically, Card6 interacted with and inhibited apoptosis signal-regulating kinase 1 (Ask1) and its subsequent downstream c-Jun N-terminal kinase/p38 signaling. Furthermore, Ask1 was sufficient to mediate Card6 function, and the interaction between Ask1 and Card6 was absolutely required for Card6 function in vivo. Adenovirus-mediated Card6 overexpression in the liver effectively ameliorated insulin resistance and hepatic steatosis in ob/ob mice. Therefore, we identified Card6 as an important negative regulator in NAFLD. Conclusion: Targeting Ask1 by Card6 may be a good strategy to develop a therapeutic method against NAFLD.

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Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4

Cited by 122 publications

References 75 publications

USP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity

USP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity

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

Caspase Recruitment Domain Protein 6 Protects Against Hepatic Steatosis and Insulin Resistance by Suppressing Apoptosis Signal–Regulating Kinase 1

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