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

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low‐grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we report that ubiquitin‐spec... Full description

Journal Title: Hepatology December 2017, Vol.66(6), pp.1866-1884
Main Author: An, Shimin
Other Authors: Zhao, Ling‐Ping , Shen, Li‐Jun , Wang, Siyuan , Zhang, Kuo , Qi, Yu , Zheng, Jilin , Zhang, Xiao‐Jing , Zhu, Xue‐Yong , Bao, Rong , Yang, Ling , Lu, Yue‐Xin , She, Zhi‐Gang , Tang, Yi‐Da
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ID: ISSN: 0270-9139 ; E-ISSN: 1527-3350 ; DOI: 10.1002/hep.29375
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recordid: wj10.1002/hep.29375
title: USP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity
format: Article
creator:
  • An, Shimin
  • Zhao, Ling‐Ping
  • Shen, Li‐Jun
  • Wang, Siyuan
  • Zhang, Kuo
  • Qi, Yu
  • Zheng, Jilin
  • Zhang, Xiao‐Jing
  • Zhu, Xue‐Yong
  • Bao, Rong
  • Yang, Ling
  • Lu, Yue‐Xin
  • She, Zhi‐Gang
  • Tang, Yi‐Da
subjects:
  • Muridae
  • Usp18 Protein
  • Ubiquitin-Specific Proteinase
  • Insulin Resistance
  • Exploration
  • Tak1 Protein
  • C-Jun Protein
  • High Fat Diet
  • Insulin
  • Liver
  • Fatty Liver
  • Lipid Metabolism
  • Transgenic Animals
  • Transcription Factors
  • Ubiquitin
  • Steatosis
  • Liver Diseases
  • Transgenic Mice
  • Rodents
  • Inflammation
  • Metabolic Disorders
ispartof: Hepatology, December 2017, Vol.66(6), pp.1866-1884
description: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low‐grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we report that ubiquitin‐specific protease 18 (USP18), a member of the deubiquitinating enzyme family, plays regulatory roles in NAFLD progression. Expression of USP18 was down‐regulated in the livers of nonalcoholic steatohepatitis patients and high‐fat diet (HFD)–induced or genetically obese mice. When challenged with HFD, hepatocyte‐specific USP18 transgenic mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18–hepatocyte‐specific transgenic mice and promoted in USP18–hepatocyte‐specific knockout mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating transforming growth factorβ‐activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream c‐Jun N‐terminal kinase and nuclear factor kappa B signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD‐fed USP18–hepatocyte‐specific knockout mice administered a TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD‐fed mice injected with active‐site mutant USP18 failed to inhibit hepatic steatosis. USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance, and the inflammatory response. (H 2017;66:1866–1884)
language:
source:
identifier: ISSN: 0270-9139 ; E-ISSN: 1527-3350 ; DOI: 10.1002/hep.29375
fulltext: fulltext
issn:
  • 0270-9139
  • 02709139
  • 1527-3350
  • 15273350
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titleUSP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity
creatorAn, Shimin ; Zhao, Ling‐Ping ; Shen, Li‐Jun ; Wang, Siyuan ; Zhang, Kuo ; Qi, Yu ; Zheng, Jilin ; Zhang, Xiao‐Jing ; Zhu, Xue‐Yong ; Bao, Rong ; Yang, Ling ; Lu, Yue‐Xin ; She, Zhi‐Gang ; Tang, Yi‐Da
ispartofHepatology, December 2017, Vol.66(6), pp.1866-1884
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descriptionNonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low‐grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we report that ubiquitin‐specific protease 18 (USP18), a member of the deubiquitinating enzyme family, plays regulatory roles in NAFLD progression. Expression of USP18 was down‐regulated in the livers of nonalcoholic steatohepatitis patients and high‐fat diet (HFD)–induced or genetically obese mice. When challenged with HFD, hepatocyte‐specific USP18 transgenic mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18–hepatocyte‐specific transgenic mice and promoted in USP18–hepatocyte‐specific knockout mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating transforming growth factorβ‐activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream c‐Jun N‐terminal kinase and nuclear factor kappa B signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD‐fed USP18–hepatocyte‐specific knockout mice administered a TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD‐fed mice injected with active‐site mutant USP18 failed to inhibit hepatic steatosis. USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance, and the inflammatory response. (H 2017;66:1866–1884)
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subjectMuridae ; Usp18 Protein ; Ubiquitin-Specific Proteinase ; Insulin Resistance ; Exploration ; Tak1 Protein ; C-Jun Protein ; High Fat Diet ; Insulin ; Liver ; Fatty Liver ; Lipid Metabolism ; Transgenic Animals ; Transcription Factors ; Ubiquitin ; Steatosis ; Liver Diseases ; Transgenic Mice ; Rodents ; Inflammation ; Metabolic Disorders;
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titleUSP18 protects against hepatic steatosis and insulin resistance through its deubiquitinating activity
descriptionNonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low‐grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we report that ubiquitin‐specific protease 18 (USP18), a member of the deubiquitinating enzyme family, plays regulatory roles in NAFLD progression. Expression of USP18 was down‐regulated in the livers of nonalcoholic steatohepatitis patients and high‐fat diet (HFD)–induced or genetically obese mice. When challenged with HFD, hepatocyte‐specific USP18 transgenic mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18–hepatocyte‐specific transgenic mice and promoted in USP18–hepatocyte‐specific knockout mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating transforming growth factorβ‐activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream c‐Jun N‐terminal kinase and nuclear factor kappa B signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD‐fed USP18–hepatocyte‐specific knockout mice administered a TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD‐fed mice injected with active‐site mutant USP18 failed to inhibit hepatic steatosis. USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance, and the inflammatory response. (H 2017;66:1866–1884)
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abstractNonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity, and chronic low‐grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we report that ubiquitin‐specific protease 18 (USP18), a member of the deubiquitinating enzyme family, plays regulatory roles in NAFLD progression. Expression of USP18 was down‐regulated in the livers of nonalcoholic steatohepatitis patients and high‐fat diet (HFD)–induced or genetically obese mice. When challenged with HFD, hepatocyte‐specific USP18 transgenic mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18–hepatocyte‐specific transgenic mice and promoted in USP18–hepatocyte‐specific knockout mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating transforming growth factorβ‐activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream c‐Jun N‐terminal kinase and nuclear factor kappa B signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD‐fed USP18–hepatocyte‐specific knockout mice administered a TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD‐fed mice injected with active‐site mutant USP18 failed to inhibit hepatic steatosis. USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance, and the inflammatory response. (H 2017;66:1866–1884)
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pages1866-1884
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