De-silencing Grb10 contributes to acute ER stress-induced steatosis in mouse liver
The growth factor receptor bound protein GRB10 is an imprinted gene product and a key negative regulator of the insulin, IGF1 and mTORC1 signaling pathways. GRB10 is highly expressed in mouse fetal liver but almost completely silenced in adult mice, suggesting a potential detrimental role of this pr...
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| Veröffentlicht in: | Journal of molecular endocrinology 2018-05, Vol.60 (4), p.285-297 |
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| container_title | Journal of molecular endocrinology |
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| creator | Luo, Liping Jiang, Wanxiang Liu, Hui Bu, Jicheng Tang, Ping Du, Chongyangzi Xu, Zhipeng Luo, Hairong Liu, Bilian Xiao, Bo Zhou, Zhiguang Liu, Feng |
| description | The growth factor receptor bound protein GRB10 is an imprinted gene product and a key negative regulator of the insulin, IGF1 and mTORC1 signaling pathways. GRB10 is highly expressed in mouse fetal liver but almost completely silenced in adult mice, suggesting a potential detrimental role of this protein in adult liver function. Here we show that the Grb10 gene could be reactivated in adult mouse liver by acute endoplasmic reticulum stress (ER stress) such as tunicamycin or a short-term high-fat diet (HFD) challenge, concurrently with increased unfolded protein response (UPR) and hepatosteatosis. Lipogenic gene expression and acute ER stress-induced hepatosteatosis were significantly suppressed in the liver of the liver-specific GRB10 knockout mice, uncovering a key role of Grb10 reactivation in acute ER stress-induced hepatic lipid dysregulation. Mechanically, acute ER stress induces Grb10 reactivation via an ATF4-mediated increase in Grb10 gene transcription. Our study demonstrates for the first time that the silenced Grb10 gene can be reactivated by acute ER stress and its reactivation plays an important role in the early development of hepatic steatosis. |
| doi_str_mv | 10.1530/JME-18-0018 |
| format | Article |
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GRB10 is highly expressed in mouse fetal liver but almost completely silenced in adult mice, suggesting a potential detrimental role of this protein in adult liver function. Here we show that the Grb10 gene could be reactivated in adult mouse liver by acute endoplasmic reticulum stress (ER stress) such as tunicamycin or a short-term high-fat diet (HFD) challenge, concurrently with increased unfolded protein response (UPR) and hepatosteatosis. Lipogenic gene expression and acute ER stress-induced hepatosteatosis were significantly suppressed in the liver of the liver-specific GRB10 knockout mice, uncovering a key role of Grb10 reactivation in acute ER stress-induced hepatic lipid dysregulation. Mechanically, acute ER stress induces Grb10 reactivation via an ATF4-mediated increase in Grb10 gene transcription. Our study demonstrates for the first time that the silenced Grb10 gene can be reactivated by acute ER stress and its reactivation plays an important role in the early development of hepatic steatosis.</description><identifier>ISSN: 0952-5041</identifier><identifier>EISSN: 1479-6813</identifier><identifier>DOI: 10.1530/JME-18-0018</identifier><identifier>PMID: 29555819</identifier><language>eng</language><publisher>England: Bioscientifica Ltd</publisher><subject>Endoplasmic reticulum ; Fatty liver ; Fetuses ; Gene expression ; GRB10 gene ; High fat diet ; Insulin ; Insulin-like growth factor I ; Liver ; Protein folding ; Proteins ; Rodents ; Steatosis ; Transcription ; Tunicamycin</subject><ispartof>Journal of molecular endocrinology, 2018-05, Vol.60 (4), p.285-297</ispartof><rights>2018 Society for Endocrinology</rights><rights>2018 Society for Endocrinology.</rights><rights>Copyright Society for Endocrinology & BioScientifica Ltd. May 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b396t-6e657eb91b74e99a9752cae9726ac8822dab0650f84f4608ee57426cc212500e3</citedby><cites>FETCH-LOGICAL-b396t-6e657eb91b74e99a9752cae9726ac8822dab0650f84f4608ee57426cc212500e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3936,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29555819$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Luo, Liping</creatorcontrib><creatorcontrib>Jiang, Wanxiang</creatorcontrib><creatorcontrib>Liu, Hui</creatorcontrib><creatorcontrib>Bu, Jicheng</creatorcontrib><creatorcontrib>Tang, Ping</creatorcontrib><creatorcontrib>Du, Chongyangzi</creatorcontrib><creatorcontrib>Xu, Zhipeng</creatorcontrib><creatorcontrib>Luo, Hairong</creatorcontrib><creatorcontrib>Liu, Bilian</creatorcontrib><creatorcontrib>Xiao, Bo</creatorcontrib><creatorcontrib>Zhou, Zhiguang</creatorcontrib><creatorcontrib>Liu, Feng</creatorcontrib><title>De-silencing Grb10 contributes to acute ER stress-induced steatosis in mouse liver</title><title>Journal of molecular endocrinology</title><addtitle>J Mol Endocrinol</addtitle><description>The growth factor receptor bound protein GRB10 is an imprinted gene product and a key negative regulator of the insulin, IGF1 and mTORC1 signaling pathways. GRB10 is highly expressed in mouse fetal liver but almost completely silenced in adult mice, suggesting a potential detrimental role of this protein in adult liver function. Here we show that the Grb10 gene could be reactivated in adult mouse liver by acute endoplasmic reticulum stress (ER stress) such as tunicamycin or a short-term high-fat diet (HFD) challenge, concurrently with increased unfolded protein response (UPR) and hepatosteatosis. Lipogenic gene expression and acute ER stress-induced hepatosteatosis were significantly suppressed in the liver of the liver-specific GRB10 knockout mice, uncovering a key role of Grb10 reactivation in acute ER stress-induced hepatic lipid dysregulation. Mechanically, acute ER stress induces Grb10 reactivation via an ATF4-mediated increase in Grb10 gene transcription. Our study demonstrates for the first time that the silenced Grb10 gene can be reactivated by acute ER stress and its reactivation plays an important role in the early development of hepatic steatosis.</description><subject>Endoplasmic reticulum</subject><subject>Fatty liver</subject><subject>Fetuses</subject><subject>Gene expression</subject><subject>GRB10 gene</subject><subject>High fat diet</subject><subject>Insulin</subject><subject>Insulin-like growth factor I</subject><subject>Liver</subject><subject>Protein folding</subject><subject>Proteins</subject><subject>Rodents</subject><subject>Steatosis</subject><subject>Transcription</subject><subject>Tunicamycin</subject><issn>0952-5041</issn><issn>1479-6813</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp90EtLxDAUBeAgio6PlXsJuBEkmps2TbKUcXyhCIOuQ5q5lUin1aQV_PdmGHXhwkVIAh-Hew8hh8DPQBb8_O5hxkAzzkFvkAmUyrBKQ7FJJtxIwSQvYYfspvSahQRVbpMdYaSUGsyEzC-RpdBi50P3Qq9jDZz6vhtiqMcBEx166nx-0dmcpiFiSix0i9HjIn_RDX0KiYaOLvsxIW3DB8Z9stW4NuHB971Hnq9mT9Mbdv94fTu9uGd1YaqBVVhJhbWBWpVojDNKCu_QKFE5r7UQC1fzSvJGl01ZcY0oVSkq7wUIyTkWe-RknfsW-_cR02CXIXlsW9dhnsaKvK4uFC9kpsd_6Gs_xi5PZwUoAYXMJ6vTtfKxTyliY99iWLr4aYHbVdU2V21B21XVWR99Z471Ehe_9qfbDGAN6tAnH7AbQhO8-zf0C-1Th0k</recordid><startdate>201805</startdate><enddate>201805</enddate><creator>Luo, Liping</creator><creator>Jiang, Wanxiang</creator><creator>Liu, Hui</creator><creator>Bu, Jicheng</creator><creator>Tang, Ping</creator><creator>Du, Chongyangzi</creator><creator>Xu, Zhipeng</creator><creator>Luo, Hairong</creator><creator>Liu, Bilian</creator><creator>Xiao, Bo</creator><creator>Zhou, Zhiguang</creator><creator>Liu, Feng</creator><general>Bioscientifica Ltd</general><general>Society for Endocrinology & BioScientifica Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201805</creationdate><title>De-silencing Grb10 contributes to acute ER stress-induced steatosis in mouse liver</title><author>Luo, Liping ; 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GRB10 is highly expressed in mouse fetal liver but almost completely silenced in adult mice, suggesting a potential detrimental role of this protein in adult liver function. Here we show that the Grb10 gene could be reactivated in adult mouse liver by acute endoplasmic reticulum stress (ER stress) such as tunicamycin or a short-term high-fat diet (HFD) challenge, concurrently with increased unfolded protein response (UPR) and hepatosteatosis. Lipogenic gene expression and acute ER stress-induced hepatosteatosis were significantly suppressed in the liver of the liver-specific GRB10 knockout mice, uncovering a key role of Grb10 reactivation in acute ER stress-induced hepatic lipid dysregulation. Mechanically, acute ER stress induces Grb10 reactivation via an ATF4-mediated increase in Grb10 gene transcription. 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| subjects | Endoplasmic reticulum Fatty liver Fetuses Gene expression GRB10 gene High fat diet Insulin Insulin-like growth factor I Liver Protein folding Proteins Rodents Steatosis Transcription Tunicamycin |
| title | De-silencing Grb10 contributes to acute ER stress-induced steatosis in mouse liver |
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