Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis
ObjectiveLiver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a...
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| Veröffentlicht in: | Gut 2024-01, Vol.73 (5), p.810-824 |
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| creator | Kong, Ming Zhou, Junjing Kang, Aoqi Kuai, Yameng Xu, Huihui Li, Min Miao, Xiulian Guo, Yan Fan, Zhiwen Xu, Yong Li, Zilong |
| description | ObjectiveLiver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis.DesignHSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the Suv39h1 f/f mice to the Lrat-Cre mice or the Postn-CreERT2 mice. Liver fibrosis was induced by CCl4 injection or bile duct ligation.ResultsWe report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme.ConclusionsOur data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis. |
| doi_str_mv | 10.1136/gutjnl-2023-329671 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2928927007</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2928927007</sourcerecordid><originalsourceid>FETCH-LOGICAL-b398t-125479f82383b22842fbf7817b43d917ea0d5620f3019cd3a24b517f222f2b653</originalsourceid><addsrcrecordid>eNp9kU9v1DAQxS0EotvCF-CALHHhkmKPk9hzRFWhSJU4AGfLTuxdr_JnsZ2V-u1xlFIkDj2NZvSbN89-hLzj7Jpz0X7aL_k4DRUwEJUAbCV_QXa8blXplHpJdoxxWTWyxgtymdKRMaYU8tfkQiguW4VqR053IeV5cnR0-fAw5Gim5F00ydEfy1nggdPo9stgskv04E4mh46m7IZ1QrtSqelyOJf5PFEz9TQkmk3cu2zs4GiY6BDOLlIfbJxTSG_IK2-G5N4-1ivy68vtz5u76v771283n-8rK1DlikNTS_QKhBIWQNXgrZfFtq1Fj1w6w_qmBeYF49j1wkBtGy49AHiwbSOuyMdN9xTn34tLWY8hrX7N5OYlaUBQCJIxWdAP_6HHeYlTcacFKx-LHBGfowAZylZgvVKwUV15bYrO61MMo4kPmjO9pqa31PSamt5SK0vvH6UXO7r-aeVvTAW43gA7Hv-dfUbxD3OPomg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2909763949</pqid></control><display><type>article</type><title>Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis</title><source>PubMed Central</source><creator>Kong, Ming ; Zhou, Junjing ; Kang, Aoqi ; Kuai, Yameng ; Xu, Huihui ; Li, Min ; Miao, Xiulian ; Guo, Yan ; Fan, Zhiwen ; Xu, Yong ; Li, Zilong</creator><creatorcontrib>Kong, Ming ; Zhou, Junjing ; Kang, Aoqi ; Kuai, Yameng ; Xu, Huihui ; Li, Min ; Miao, Xiulian ; Guo, Yan ; Fan, Zhiwen ; Xu, Yong ; Li, Zilong</creatorcontrib><description>ObjectiveLiver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis.DesignHSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the Suv39h1 f/f mice to the Lrat-Cre mice or the Postn-CreERT2 mice. Liver fibrosis was induced by CCl4 injection or bile duct ligation.ResultsWe report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme.ConclusionsOur data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis.</description><identifier>ISSN: 0017-5749</identifier><identifier>ISSN: 1468-3288</identifier><identifier>EISSN: 1468-3288</identifier><identifier>DOI: 10.1136/gutjnl-2023-329671</identifier><identifier>PMID: 38176898</identifier><language>eng</language><publisher>England: BMJ Publishing Group Ltd and British Society of Gastroenterology</publisher><subject>Animal models ; Bile ducts ; Carbon tetrachloride ; Cell activation ; Cell culture ; Cirrhosis ; Cross-breeding ; Epigenetics ; Extracellular matrix ; Fibrosis ; Heme oxygenase (decyclizing) ; hepatic fibrosis ; Hepatocytes ; Hepatology ; Histone methyltransferase ; Homeostasis ; Injuries ; Liver cancer ; Liver cirrhosis ; Liver diseases ; Pharmaceuticals ; Proteins ; Stellate cells ; Transcriptomics ; Vitamin A</subject><ispartof>Gut, 2024-01, Vol.73 (5), p.810-824</ispartof><rights>Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.</rights><rights>2024 Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-b398t-125479f82383b22842fbf7817b43d917ea0d5620f3019cd3a24b517f222f2b653</citedby><cites>FETCH-LOGICAL-b398t-125479f82383b22842fbf7817b43d917ea0d5620f3019cd3a24b517f222f2b653</cites><orcidid>0000-0003-1470-9371</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38176898$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kong, Ming</creatorcontrib><creatorcontrib>Zhou, Junjing</creatorcontrib><creatorcontrib>Kang, Aoqi</creatorcontrib><creatorcontrib>Kuai, Yameng</creatorcontrib><creatorcontrib>Xu, Huihui</creatorcontrib><creatorcontrib>Li, Min</creatorcontrib><creatorcontrib>Miao, Xiulian</creatorcontrib><creatorcontrib>Guo, Yan</creatorcontrib><creatorcontrib>Fan, Zhiwen</creatorcontrib><creatorcontrib>Xu, Yong</creatorcontrib><creatorcontrib>Li, Zilong</creatorcontrib><title>Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis</title><title>Gut</title><addtitle>Gut</addtitle><addtitle>Gut</addtitle><description>ObjectiveLiver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis.DesignHSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the Suv39h1 f/f mice to the Lrat-Cre mice or the Postn-CreERT2 mice. Liver fibrosis was induced by CCl4 injection or bile duct ligation.ResultsWe report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme.ConclusionsOur data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis.</description><subject>Animal models</subject><subject>Bile ducts</subject><subject>Carbon tetrachloride</subject><subject>Cell activation</subject><subject>Cell culture</subject><subject>Cirrhosis</subject><subject>Cross-breeding</subject><subject>Epigenetics</subject><subject>Extracellular matrix</subject><subject>Fibrosis</subject><subject>Heme oxygenase (decyclizing)</subject><subject>hepatic fibrosis</subject><subject>Hepatocytes</subject><subject>Hepatology</subject><subject>Histone methyltransferase</subject><subject>Homeostasis</subject><subject>Injuries</subject><subject>Liver cancer</subject><subject>Liver cirrhosis</subject><subject>Liver diseases</subject><subject>Pharmaceuticals</subject><subject>Proteins</subject><subject>Stellate cells</subject><subject>Transcriptomics</subject><subject>Vitamin A</subject><issn>0017-5749</issn><issn>1468-3288</issn><issn>1468-3288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kU9v1DAQxS0EotvCF-CALHHhkmKPk9hzRFWhSJU4AGfLTuxdr_JnsZ2V-u1xlFIkDj2NZvSbN89-hLzj7Jpz0X7aL_k4DRUwEJUAbCV_QXa8blXplHpJdoxxWTWyxgtymdKRMaYU8tfkQiguW4VqR053IeV5cnR0-fAw5Gim5F00ydEfy1nggdPo9stgskv04E4mh46m7IZ1QrtSqelyOJf5PFEz9TQkmk3cu2zs4GiY6BDOLlIfbJxTSG_IK2-G5N4-1ivy68vtz5u76v771283n-8rK1DlikNTS_QKhBIWQNXgrZfFtq1Fj1w6w_qmBeYF49j1wkBtGy49AHiwbSOuyMdN9xTn34tLWY8hrX7N5OYlaUBQCJIxWdAP_6HHeYlTcacFKx-LHBGfowAZylZgvVKwUV15bYrO61MMo4kPmjO9pqa31PSamt5SK0vvH6UXO7r-aeVvTAW43gA7Hv-dfUbxD3OPomg</recordid><startdate>20240104</startdate><enddate>20240104</enddate><creator>Kong, Ming</creator><creator>Zhou, Junjing</creator><creator>Kang, Aoqi</creator><creator>Kuai, Yameng</creator><creator>Xu, Huihui</creator><creator>Li, Min</creator><creator>Miao, Xiulian</creator><creator>Guo, Yan</creator><creator>Fan, Zhiwen</creator><creator>Xu, Yong</creator><creator>Li, Zilong</creator><general>BMJ Publishing Group Ltd and British Society of Gastroenterology</general><general>BMJ Publishing Group LTD</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>BTHHO</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>PRINS</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-1470-9371</orcidid></search><sort><creationdate>20240104</creationdate><title>Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis</title><author>Kong, Ming ; Zhou, Junjing ; Kang, Aoqi ; Kuai, Yameng ; Xu, Huihui ; Li, Min ; Miao, Xiulian ; Guo, Yan ; Fan, Zhiwen ; Xu, Yong ; Li, Zilong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-b398t-125479f82383b22842fbf7817b43d917ea0d5620f3019cd3a24b517f222f2b653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animal models</topic><topic>Bile ducts</topic><topic>Carbon tetrachloride</topic><topic>Cell activation</topic><topic>Cell culture</topic><topic>Cirrhosis</topic><topic>Cross-breeding</topic><topic>Epigenetics</topic><topic>Extracellular matrix</topic><topic>Fibrosis</topic><topic>Heme oxygenase (decyclizing)</topic><topic>hepatic fibrosis</topic><topic>Hepatocytes</topic><topic>Hepatology</topic><topic>Histone methyltransferase</topic><topic>Homeostasis</topic><topic>Injuries</topic><topic>Liver cancer</topic><topic>Liver cirrhosis</topic><topic>Liver diseases</topic><topic>Pharmaceuticals</topic><topic>Proteins</topic><topic>Stellate cells</topic><topic>Transcriptomics</topic><topic>Vitamin A</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kong, Ming</creatorcontrib><creatorcontrib>Zhou, Junjing</creatorcontrib><creatorcontrib>Kang, Aoqi</creatorcontrib><creatorcontrib>Kuai, Yameng</creatorcontrib><creatorcontrib>Xu, Huihui</creatorcontrib><creatorcontrib>Li, Min</creatorcontrib><creatorcontrib>Miao, Xiulian</creatorcontrib><creatorcontrib>Guo, Yan</creatorcontrib><creatorcontrib>Fan, Zhiwen</creatorcontrib><creatorcontrib>Xu, Yong</creatorcontrib><creatorcontrib>Li, Zilong</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>BMJ Journals</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest Science Journals</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Gut</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kong, Ming</au><au>Zhou, Junjing</au><au>Kang, Aoqi</au><au>Kuai, Yameng</au><au>Xu, Huihui</au><au>Li, Min</au><au>Miao, Xiulian</au><au>Guo, Yan</au><au>Fan, Zhiwen</au><au>Xu, Yong</au><au>Li, Zilong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis</atitle><jtitle>Gut</jtitle><stitle>Gut</stitle><addtitle>Gut</addtitle><date>2024-01-04</date><risdate>2024</risdate><volume>73</volume><issue>5</issue><spage>810</spage><epage>824</epage><pages>810-824</pages><issn>0017-5749</issn><issn>1468-3288</issn><eissn>1468-3288</eissn><abstract>ObjectiveLiver fibrosis is a prelude to a host of end-stage liver diseases. Hepatic stellate cells (HSCs), switching from a quiescent state to myofibroblasts, are the major source for excessive production of extracellular matrix proteins. In the present study, we investigated the role of Suv39h1, a lysine methyltransferase, in HSC-myofibroblast transition and the implication in liver fibrosis.DesignHSC-specific or myofibroblast-specific Suv39h1 deletion was achieved by crossbreeding the Suv39h1 f/f mice to the Lrat-Cre mice or the Postn-CreERT2 mice. Liver fibrosis was induced by CCl4 injection or bile duct ligation.ResultsWe report that Suv39h1 expression was universally upregulated during HSC-myofibroblast transition in different cell and animal models of liver fibrosis and in human cirrhotic liver tissues. Consistently, Suv39h1 knockdown blocked HSC-myofibroblast transition in vitro. HSC-specific or myofibroblast-specific deletion of Suv39h1 ameliorated liver fibrosis in mice. More importantly, Suv39h1 inhibition by a small-molecule compound chaetocin dampened HSC-myofibroblast transition in cell culture and mitigated liver fibrosis in mice. Mechanistically, Suv39h1 bound to the promoter of heme oxygenase 1 (HMOX1) and repressed HMOX1 transcription. HMOX1 depletion blunted the effects of Suv39h1 inhibition on HSC-myofibroblast transition in vitro and liver fibrosis in vivo. Transcriptomic analysis revealed that HMOX1 might contribute to HSC-myofibroblast transition by modulating retinol homeostasis. Finally, myofibroblast-specific HMOX1 overexpression attenuated liver fibrosis in both a preventive scheme and a therapeutic scheme.ConclusionsOur data demonstrate a previously unrecognised role for Suv39h1 in liver fibrosis and offer proof-of-concept of its targetability in the intervention of cirrhosis.</abstract><cop>England</cop><pub>BMJ Publishing Group Ltd and British Society of Gastroenterology</pub><pmid>38176898</pmid><doi>10.1136/gutjnl-2023-329671</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0003-1470-9371</orcidid></addata></record> |
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| subjects | Animal models Bile ducts Carbon tetrachloride Cell activation Cell culture Cirrhosis Cross-breeding Epigenetics Extracellular matrix Fibrosis Heme oxygenase (decyclizing) hepatic fibrosis Hepatocytes Hepatology Histone methyltransferase Homeostasis Injuries Liver cancer Liver cirrhosis Liver diseases Pharmaceuticals Proteins Stellate cells Transcriptomics Vitamin A |
| title | Histone methyltransferase Suv39h1 regulates hepatic stellate cell activation and is targetable in liver fibrosis |
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