The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis
Tripartite motif 8 (TRIM8), an E3 ligase ubiquitously expressed in various cells, is closely involved in innate immunity. However, its role in nonalcoholic steatohepatitis is largely unknown. Here, we report evidence that TRIM8 is a robust enhancer of steatohepatitis and its complications induced by...
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Veröffentlicht in: | Hepatology (Baltimore, Md.) Md.), 2017-05, Vol.65 (5), p.1492-1511 |
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creator | Yan, Feng‐Juan Zhang, Xiao‐Jing Wang, Wen‐Xin Ji, Yan‐Xiao Wang, Pi‐Xiao Yang, Yang Gong, Jun Shen, Li‐Jun Zhu, Xue‐Yong Huang, Zan Li, Hongliang |
description | Tripartite motif 8 (TRIM8), an E3 ligase ubiquitously expressed in various cells, is closely involved in innate immunity. However, its role in nonalcoholic steatohepatitis is largely unknown. Here, we report evidence that TRIM8 is a robust enhancer of steatohepatitis and its complications induced by a high‐fat diet or a genetic deficiency (ob/ob). Using gain‐of‐function and loss‐of‐function approaches, we observed dramatic exacerbation of insulin resistance, hepatic steatosis, inflammation, and fibrosis by hepatocyte‐specific TRIM8 overexpression, whereas deletion or down‐regulation of TRIM8 in hepatocytes led to a completely opposite phenotype. Furthermore, investigations of the underlying mechanisms revealed that TRIM8 directly binds to and ubiquitinates transforming growth factor‐beta–activated kinase 1, thus promoting its phosphorylation and the activation of downstream c‐Jun N‐terminal kinase/p38 and nuclear factor κB signaling. Importantly, the participation of TRIM8 in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis was verified on the basis of its dramatically increased expression in the livers of these patients, suggesting a promising development of TRIM8 disturbance for the treatment of nonalcoholic steatohepatitis–related metabolic disorders. Conclusion: The E3 ligase TRIM8 is a potent regulator that exacerbates steatohepatitis and metabolic disorders dependent on its binding and ubiquitinating capacity on transforming growth factor‐beta–activated kinase 1. (Hepatology 2017;65:1492‐1511) |
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However, its role in nonalcoholic steatohepatitis is largely unknown. Here, we report evidence that TRIM8 is a robust enhancer of steatohepatitis and its complications induced by a high‐fat diet or a genetic deficiency (ob/ob). Using gain‐of‐function and loss‐of‐function approaches, we observed dramatic exacerbation of insulin resistance, hepatic steatosis, inflammation, and fibrosis by hepatocyte‐specific TRIM8 overexpression, whereas deletion or down‐regulation of TRIM8 in hepatocytes led to a completely opposite phenotype. Furthermore, investigations of the underlying mechanisms revealed that TRIM8 directly binds to and ubiquitinates transforming growth factor‐beta–activated kinase 1, thus promoting its phosphorylation and the activation of downstream c‐Jun N‐terminal kinase/p38 and nuclear factor κB signaling. Importantly, the participation of TRIM8 in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis was verified on the basis of its dramatically increased expression in the livers of these patients, suggesting a promising development of TRIM8 disturbance for the treatment of nonalcoholic steatohepatitis–related metabolic disorders. Conclusion: The E3 ligase TRIM8 is a potent regulator that exacerbates steatohepatitis and metabolic disorders dependent on its binding and ubiquitinating capacity on transforming growth factor‐beta–activated kinase 1. (Hepatology 2017;65:1492‐1511)</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.28971</identifier><identifier>PMID: 27981609</identifier><identifier>CODEN: HPTLD9</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Animals ; c-Jun protein ; Carrier Proteins - metabolism ; Clonal deletion ; Diet, High-Fat ; Fatty liver ; Fatty Liver - enzymology ; Fibrosis ; Growth factors ; Hepatocytes ; Hepatology ; High fat diet ; Humans ; Innate immunity ; Insulin ; Insulin Resistance ; JNK protein ; Lipid Metabolism ; Liver - metabolism ; Liver - pathology ; Liver diseases ; Male ; MAP Kinase Kinase Kinases - metabolism ; MAP Kinase Signaling System ; Metabolic disorders ; Mice, Transgenic ; Nerve Tissue Proteins - metabolism ; Phosphorylation ; Steatosis ; TAK1 protein ; Transcription factors ; Ubiquitin-protein ligase ; Ubiquitination</subject><ispartof>Hepatology (Baltimore, Md.), 2017-05, Vol.65 (5), p.1492-1511</ispartof><rights>2016 by the American Association for the Study of Liver Diseases.</rights><rights>2017 by the American Association for the Study of Liver Diseases.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4141-aa2f684bdf405f33cb10ba27c863b1f4bf4703e45750e97c326af879eba6e71b3</citedby><cites>FETCH-LOGICAL-c4141-aa2f684bdf405f33cb10ba27c863b1f4bf4703e45750e97c326af879eba6e71b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.28971$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.28971$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27981609$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yan, Feng‐Juan</creatorcontrib><creatorcontrib>Zhang, Xiao‐Jing</creatorcontrib><creatorcontrib>Wang, Wen‐Xin</creatorcontrib><creatorcontrib>Ji, Yan‐Xiao</creatorcontrib><creatorcontrib>Wang, Pi‐Xiao</creatorcontrib><creatorcontrib>Yang, Yang</creatorcontrib><creatorcontrib>Gong, Jun</creatorcontrib><creatorcontrib>Shen, Li‐Jun</creatorcontrib><creatorcontrib>Zhu, Xue‐Yong</creatorcontrib><creatorcontrib>Huang, Zan</creatorcontrib><creatorcontrib>Li, Hongliang</creatorcontrib><title>The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>Tripartite motif 8 (TRIM8), an E3 ligase ubiquitously expressed in various cells, is closely involved in innate immunity. However, its role in nonalcoholic steatohepatitis is largely unknown. Here, we report evidence that TRIM8 is a robust enhancer of steatohepatitis and its complications induced by a high‐fat diet or a genetic deficiency (ob/ob). Using gain‐of‐function and loss‐of‐function approaches, we observed dramatic exacerbation of insulin resistance, hepatic steatosis, inflammation, and fibrosis by hepatocyte‐specific TRIM8 overexpression, whereas deletion or down‐regulation of TRIM8 in hepatocytes led to a completely opposite phenotype. Furthermore, investigations of the underlying mechanisms revealed that TRIM8 directly binds to and ubiquitinates transforming growth factor‐beta–activated kinase 1, thus promoting its phosphorylation and the activation of downstream c‐Jun N‐terminal kinase/p38 and nuclear factor κB signaling. Importantly, the participation of TRIM8 in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis was verified on the basis of its dramatically increased expression in the livers of these patients, suggesting a promising development of TRIM8 disturbance for the treatment of nonalcoholic steatohepatitis–related metabolic disorders. Conclusion: The E3 ligase TRIM8 is a potent regulator that exacerbates steatohepatitis and metabolic disorders dependent on its binding and ubiquitinating capacity on transforming growth factor‐beta–activated kinase 1. (Hepatology 2017;65:1492‐1511)</description><subject>Animals</subject><subject>c-Jun protein</subject><subject>Carrier Proteins - metabolism</subject><subject>Clonal deletion</subject><subject>Diet, High-Fat</subject><subject>Fatty liver</subject><subject>Fatty Liver - enzymology</subject><subject>Fibrosis</subject><subject>Growth factors</subject><subject>Hepatocytes</subject><subject>Hepatology</subject><subject>High fat diet</subject><subject>Humans</subject><subject>Innate immunity</subject><subject>Insulin</subject><subject>Insulin Resistance</subject><subject>JNK protein</subject><subject>Lipid Metabolism</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Liver diseases</subject><subject>Male</subject><subject>MAP Kinase Kinase Kinases - metabolism</subject><subject>MAP Kinase Signaling System</subject><subject>Metabolic disorders</subject><subject>Mice, Transgenic</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Phosphorylation</subject><subject>Steatosis</subject><subject>TAK1 protein</subject><subject>Transcription factors</subject><subject>Ubiquitin-protein ligase</subject><subject>Ubiquitination</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqN0T1vFDEQBmALgcgRKPgDyBINFJuMv-0yig6CEgmKo7a8e-PE0d7uYXuF8u9xcoECiYjKxTx6NZ6XkLcMThgAP73B_Qm3zrBnZMUUN50QCp6TFXADnWPCHZFXpdwCgJPcviRH3DjLNLgV8ZsbpGtBx3QdCtKa0z7kmirS3VxTpJbWkK-xFro5u2S0znSf5zZCmqayjGmiGUsqNUwD0jBtaakY6tw2Ci0lldfkRQxjwTeP7zH5_mm9Ob_orr5-_nJ-dtUNkknWhcCjtrLfRgkqCjH0DPrAzWC16FmUfZQGBEplFKAzg-A6RGsc9kGjYb04Jh8OuW29HwuW6nepDDiOYcJ5KZ618wijLGf_QRXXVnMrGn3_F72dlzy1j3jmQIDWzugnlbVOcemUbOrjQQ15LiVj9PucdiHfeQb-vkbfjuYfamz23WPi0u9w-0f-7q2B0wP4mUa8-3eSv1h_O0T-AknxpKw</recordid><startdate>201705</startdate><enddate>201705</enddate><creator>Yan, Feng‐Juan</creator><creator>Zhang, Xiao‐Jing</creator><creator>Wang, Wen‐Xin</creator><creator>Ji, Yan‐Xiao</creator><creator>Wang, Pi‐Xiao</creator><creator>Yang, Yang</creator><creator>Gong, Jun</creator><creator>Shen, Li‐Jun</creator><creator>Zhu, Xue‐Yong</creator><creator>Huang, Zan</creator><creator>Li, Hongliang</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201705</creationdate><title>The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis</title><author>Yan, Feng‐Juan ; Zhang, Xiao‐Jing ; Wang, Wen‐Xin ; Ji, Yan‐Xiao ; Wang, Pi‐Xiao ; Yang, Yang ; Gong, Jun ; Shen, Li‐Jun ; Zhu, Xue‐Yong ; Huang, Zan ; Li, Hongliang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4141-aa2f684bdf405f33cb10ba27c863b1f4bf4703e45750e97c326af879eba6e71b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>c-Jun protein</topic><topic>Carrier Proteins - metabolism</topic><topic>Clonal deletion</topic><topic>Diet, High-Fat</topic><topic>Fatty liver</topic><topic>Fatty Liver - enzymology</topic><topic>Fibrosis</topic><topic>Growth factors</topic><topic>Hepatocytes</topic><topic>Hepatology</topic><topic>High fat diet</topic><topic>Humans</topic><topic>Innate immunity</topic><topic>Insulin</topic><topic>Insulin Resistance</topic><topic>JNK protein</topic><topic>Lipid Metabolism</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Liver diseases</topic><topic>Male</topic><topic>MAP Kinase Kinase Kinases - metabolism</topic><topic>MAP Kinase Signaling System</topic><topic>Metabolic disorders</topic><topic>Mice, Transgenic</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Phosphorylation</topic><topic>Steatosis</topic><topic>TAK1 protein</topic><topic>Transcription factors</topic><topic>Ubiquitin-protein ligase</topic><topic>Ubiquitination</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yan, Feng‐Juan</creatorcontrib><creatorcontrib>Zhang, Xiao‐Jing</creatorcontrib><creatorcontrib>Wang, Wen‐Xin</creatorcontrib><creatorcontrib>Ji, Yan‐Xiao</creatorcontrib><creatorcontrib>Wang, Pi‐Xiao</creatorcontrib><creatorcontrib>Yang, Yang</creatorcontrib><creatorcontrib>Gong, Jun</creatorcontrib><creatorcontrib>Shen, Li‐Jun</creatorcontrib><creatorcontrib>Zhu, Xue‐Yong</creatorcontrib><creatorcontrib>Huang, Zan</creatorcontrib><creatorcontrib>Li, Hongliang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yan, Feng‐Juan</au><au>Zhang, Xiao‐Jing</au><au>Wang, Wen‐Xin</au><au>Ji, Yan‐Xiao</au><au>Wang, Pi‐Xiao</au><au>Yang, Yang</au><au>Gong, Jun</au><au>Shen, Li‐Jun</au><au>Zhu, Xue‐Yong</au><au>Huang, Zan</au><au>Li, Hongliang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2017-05</date><risdate>2017</risdate><volume>65</volume><issue>5</issue><spage>1492</spage><epage>1511</epage><pages>1492-1511</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><coden>HPTLD9</coden><abstract>Tripartite motif 8 (TRIM8), an E3 ligase ubiquitously expressed in various cells, is closely involved in innate immunity. However, its role in nonalcoholic steatohepatitis is largely unknown. Here, we report evidence that TRIM8 is a robust enhancer of steatohepatitis and its complications induced by a high‐fat diet or a genetic deficiency (ob/ob). Using gain‐of‐function and loss‐of‐function approaches, we observed dramatic exacerbation of insulin resistance, hepatic steatosis, inflammation, and fibrosis by hepatocyte‐specific TRIM8 overexpression, whereas deletion or down‐regulation of TRIM8 in hepatocytes led to a completely opposite phenotype. Furthermore, investigations of the underlying mechanisms revealed that TRIM8 directly binds to and ubiquitinates transforming growth factor‐beta–activated kinase 1, thus promoting its phosphorylation and the activation of downstream c‐Jun N‐terminal kinase/p38 and nuclear factor κB signaling. Importantly, the participation of TRIM8 in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis was verified on the basis of its dramatically increased expression in the livers of these patients, suggesting a promising development of TRIM8 disturbance for the treatment of nonalcoholic steatohepatitis–related metabolic disorders. Conclusion: The E3 ligase TRIM8 is a potent regulator that exacerbates steatohepatitis and metabolic disorders dependent on its binding and ubiquitinating capacity on transforming growth factor‐beta–activated kinase 1. (Hepatology 2017;65:1492‐1511)</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>27981609</pmid><doi>10.1002/hep.28971</doi><tpages>20</tpages></addata></record> |
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subjects | Animals c-Jun protein Carrier Proteins - metabolism Clonal deletion Diet, High-Fat Fatty liver Fatty Liver - enzymology Fibrosis Growth factors Hepatocytes Hepatology High fat diet Humans Innate immunity Insulin Insulin Resistance JNK protein Lipid Metabolism Liver - metabolism Liver - pathology Liver diseases Male MAP Kinase Kinase Kinases - metabolism MAP Kinase Signaling System Metabolic disorders Mice, Transgenic Nerve Tissue Proteins - metabolism Phosphorylation Steatosis TAK1 protein Transcription factors Ubiquitin-protein ligase Ubiquitination |
title | The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis |
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