Orphan nuclear receptor ERRγ is a key regulator of human fibrinogen gene expression
Fibrinogen, 1 of 13 coagulation factors responsible for normal blood clotting, is synthesized by hepatocytes. Detailed roles of the orphan nuclear receptors regulating fibrinogen gene expression have not yet been fully elucidated. Here, we identified estrogen-related receptor gamma (ERRγ) as a novel...
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| creator | Zhang, Yaochen Kim, Don-Kyu Lu, Yan Jung, Yoon Seok Lee, Ji-Min Kim, Young-Hoon Lee, Yong Soo Kim, Jina Dewidar, Bedair Jeong, Won-Il Lee, In-Kyu Cho, Sung Jin Dooley, Steven Lee, Chul-Ho Li, Xiaoying Choi, Hueng-Sik |
| description | Fibrinogen, 1 of 13 coagulation factors responsible for normal blood clotting, is synthesized by hepatocytes. Detailed roles of the orphan nuclear receptors regulating fibrinogen gene expression have not yet been fully elucidated. Here, we identified estrogen-related receptor gamma (ERRγ) as a novel transcriptional regulator of human fibrinogen gene expression. Overexpression of ERRγ specially increased fibrinogen expression in human hepatoma cell line. Cannabinoid receptor types 1(CB1R) agonist arachidonyl-2'-chloroethylamide (ACEA) up-regulated transcription of fibrinogen via induction of ERRγ, whereas knockdown of ERRγ attenuated fibrinogen expression. Deletion analyses of the fibrinogen γ (FGG) gene promoter and ChIP assays revealed binding sites of ERRγ on human fibrinogen γ gene promoter. Moreover, overexpression of ERRγ was sufficient to increase fibrinogen gene expression, whereas treatment with GSK5182, a selective inverse agonist of ERRγ led to its attenuation in cell culture. Finally, fibrinogen and ERRγ gene expression were elevated in liver tissue of obese patients suggesting a conservation of this mechanism. Overall, this study elucidates a molecular mechanism linking CB1R signaling, ERRγ expression and fibrinogen gene transcription. GSK5182 may have therapeutic potential to treat hyperfibrinogenemia. |
| doi_str_mv | 10.1371/journal.pone.0182141 |
| format | Article |
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Detailed roles of the orphan nuclear receptors regulating fibrinogen gene expression have not yet been fully elucidated. Here, we identified estrogen-related receptor gamma (ERRγ) as a novel transcriptional regulator of human fibrinogen gene expression. Overexpression of ERRγ specially increased fibrinogen expression in human hepatoma cell line. Cannabinoid receptor types 1(CB1R) agonist arachidonyl-2'-chloroethylamide (ACEA) up-regulated transcription of fibrinogen via induction of ERRγ, whereas knockdown of ERRγ attenuated fibrinogen expression. Deletion analyses of the fibrinogen γ (FGG) gene promoter and ChIP assays revealed binding sites of ERRγ on human fibrinogen γ gene promoter. Moreover, overexpression of ERRγ was sufficient to increase fibrinogen gene expression, whereas treatment with GSK5182, a selective inverse agonist of ERRγ led to its attenuation in cell culture. Finally, fibrinogen and ERRγ gene expression were elevated in liver tissue of obese patients suggesting a conservation of this mechanism. Overall, this study elucidates a molecular mechanism linking CB1R signaling, ERRγ expression and fibrinogen gene transcription. GSK5182 may have therapeutic potential to treat hyperfibrinogenemia.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0182141</identifier><identifier>PMID: 28750085</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Aged ; Animals ; Binding sites ; Biology and Life Sciences ; Blood clots ; Blood coagulation ; Cannabinoid CB1 receptors ; Cell culture ; Clonal deletion ; Clotting ; Coagulation ; Conservation ; Diabetes ; Endocrinology ; Estrogens ; Fibrinogen ; Fibrinogen - genetics ; Fibrinogen - metabolism ; Gene deletion ; Gene expression ; Gene Expression Regulation ; Gene Knockdown Techniques ; Hep G2 Cells ; Hepatocytes ; Hepatoma ; Hospitals ; Humans ; Insulin ; Kinases ; Laboratories ; Ligands ; Liver ; Liver - metabolism ; Liver diseases ; Medicine ; Medicine and Health Sciences ; Metabolic disorders ; Mice ; Middle Aged ; Non-alcoholic Fatty Liver Disease - genetics ; Nuclear receptors ; Obesity ; Obesity - genetics ; Orphan nuclear receptors ; Phosphatase ; Promoter Regions, Genetic - genetics ; R&D ; Receptor, Cannabinoid, CB1 - metabolism ; Receptors ; Receptors, Estrogen - metabolism ; Research & development ; Research and Analysis Methods ; Rodents ; Signaling ; Transcription ; Transcription, Genetic</subject><ispartof>PloS one, 2017-07, Vol.12 (7), p.e0182141-e0182141</ispartof><rights>2017 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Zhang et al 2017 Zhang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4411-4311b8b0b005487f23578807348f97e2bfb1570ba864272e46bab68783a42b153</citedby><cites>FETCH-LOGICAL-c4411-4311b8b0b005487f23578807348f97e2bfb1570ba864272e46bab68783a42b153</cites><orcidid>0000-0002-3163-1572</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531639/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531639/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28750085$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Villena, Josep A.</contributor><creatorcontrib>Zhang, Yaochen</creatorcontrib><creatorcontrib>Kim, Don-Kyu</creatorcontrib><creatorcontrib>Lu, Yan</creatorcontrib><creatorcontrib>Jung, Yoon Seok</creatorcontrib><creatorcontrib>Lee, Ji-Min</creatorcontrib><creatorcontrib>Kim, Young-Hoon</creatorcontrib><creatorcontrib>Lee, Yong Soo</creatorcontrib><creatorcontrib>Kim, Jina</creatorcontrib><creatorcontrib>Dewidar, Bedair</creatorcontrib><creatorcontrib>Jeong, Won-Il</creatorcontrib><creatorcontrib>Lee, In-Kyu</creatorcontrib><creatorcontrib>Cho, Sung Jin</creatorcontrib><creatorcontrib>Dooley, Steven</creatorcontrib><creatorcontrib>Lee, Chul-Ho</creatorcontrib><creatorcontrib>Li, Xiaoying</creatorcontrib><creatorcontrib>Choi, Hueng-Sik</creatorcontrib><title>Orphan nuclear receptor ERRγ is a key regulator of human fibrinogen gene expression</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Fibrinogen, 1 of 13 coagulation factors responsible for normal blood clotting, is synthesized by hepatocytes. Detailed roles of the orphan nuclear receptors regulating fibrinogen gene expression have not yet been fully elucidated. Here, we identified estrogen-related receptor gamma (ERRγ) as a novel transcriptional regulator of human fibrinogen gene expression. Overexpression of ERRγ specially increased fibrinogen expression in human hepatoma cell line. Cannabinoid receptor types 1(CB1R) agonist arachidonyl-2'-chloroethylamide (ACEA) up-regulated transcription of fibrinogen via induction of ERRγ, whereas knockdown of ERRγ attenuated fibrinogen expression. Deletion analyses of the fibrinogen γ (FGG) gene promoter and ChIP assays revealed binding sites of ERRγ on human fibrinogen γ gene promoter. Moreover, overexpression of ERRγ was sufficient to increase fibrinogen gene expression, whereas treatment with GSK5182, a selective inverse agonist of ERRγ led to its attenuation in cell culture. Finally, fibrinogen and ERRγ gene expression were elevated in liver tissue of obese patients suggesting a conservation of this mechanism. Overall, this study elucidates a molecular mechanism linking CB1R signaling, ERRγ expression and fibrinogen gene transcription. GSK5182 may have therapeutic potential to treat hyperfibrinogenemia.</description><subject>Adult</subject><subject>Aged</subject><subject>Animals</subject><subject>Binding sites</subject><subject>Biology and Life Sciences</subject><subject>Blood clots</subject><subject>Blood coagulation</subject><subject>Cannabinoid CB1 receptors</subject><subject>Cell culture</subject><subject>Clonal deletion</subject><subject>Clotting</subject><subject>Coagulation</subject><subject>Conservation</subject><subject>Diabetes</subject><subject>Endocrinology</subject><subject>Estrogens</subject><subject>Fibrinogen</subject><subject>Fibrinogen - genetics</subject><subject>Fibrinogen - metabolism</subject><subject>Gene deletion</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Gene Knockdown Techniques</subject><subject>Hep G2 Cells</subject><subject>Hepatocytes</subject><subject>Hepatoma</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Insulin</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Ligands</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Liver diseases</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Metabolic disorders</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Non-alcoholic Fatty Liver Disease - genetics</subject><subject>Nuclear receptors</subject><subject>Obesity</subject><subject>Obesity - genetics</subject><subject>Orphan nuclear receptors</subject><subject>Phosphatase</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>R&D</subject><subject>Receptor, Cannabinoid, CB1 - metabolism</subject><subject>Receptors</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Research & development</subject><subject>Research and Analysis Methods</subject><subject>Rodents</subject><subject>Signaling</subject><subject>Transcription</subject><subject>Transcription, Genetic</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNptUl1rFDEUDaLYD_0HogO--LLbfCfzIpRSa6FQKPU5JNmb3VlnkzHZEfu7_B_-JrPutLTSh5Bw7znn3hMOQu8InhOmyMk6jTnafj6kCHNMNCWcvECHpGV0JilmLx-9D9BRKWuMBdNSvkYHVCuBsRaH6PY6Dysbmzj6HmxuMngYtik35zc3f343XWls8x3uan059nbXSKFZjZtKCZ3LXUxLiE090MCvIUMpXYpv0Ktg-wJvp_sYfftyfnv2dXZ1fXF5dno185wTMuOMEKcddnUxrlWgTCitsWJch1YBdcERobCzWnKqKHDprJNaaWY5rS12jD7sdYc-FTN9SDEUEyVoq1tWEZd7xCLZtRlyt7H5ziTbmX-FlJfG5m1XvRvPPNMUBPPBcguilWCrEgOlFkGqRdX6PE0b3QYWHuI22_6J6NNO7FZmmX4aIRiRrK0CnyaBnH6MULZm0xUPfW8jpLEY0lIuMRecVOjH_6DPu-N7lM-plAzhYRmCzS4k9yyzC4mZQlJp7x8beSDdp4L9Bbanui8</recordid><startdate>20170701</startdate><enddate>20170701</enddate><creator>Zhang, 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nuclear receptor ERRγ is a key regulator of human fibrinogen gene expression</title><author>Zhang, Yaochen ; Kim, Don-Kyu ; Lu, Yan ; Jung, Yoon Seok ; Lee, Ji-Min ; Kim, Young-Hoon ; Lee, Yong Soo ; Kim, Jina ; Dewidar, Bedair ; Jeong, Won-Il ; Lee, In-Kyu ; Cho, Sung Jin ; Dooley, Steven ; Lee, Chul-Ho ; Li, Xiaoying ; Choi, Hueng-Sik</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4411-4311b8b0b005487f23578807348f97e2bfb1570ba864272e46bab68783a42b153</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Animals</topic><topic>Binding sites</topic><topic>Biology and Life Sciences</topic><topic>Blood clots</topic><topic>Blood coagulation</topic><topic>Cannabinoid CB1 receptors</topic><topic>Cell culture</topic><topic>Clonal deletion</topic><topic>Clotting</topic><topic>Coagulation</topic><topic>Conservation</topic><topic>Diabetes</topic><topic>Endocrinology</topic><topic>Estrogens</topic><topic>Fibrinogen</topic><topic>Fibrinogen - genetics</topic><topic>Fibrinogen - metabolism</topic><topic>Gene deletion</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Gene Knockdown Techniques</topic><topic>Hep G2 Cells</topic><topic>Hepatocytes</topic><topic>Hepatoma</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Insulin</topic><topic>Kinases</topic><topic>Laboratories</topic><topic>Ligands</topic><topic>Liver</topic><topic>Liver - metabolism</topic><topic>Liver diseases</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Metabolic disorders</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Non-alcoholic Fatty Liver Disease - genetics</topic><topic>Nuclear receptors</topic><topic>Obesity</topic><topic>Obesity - 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Yan</au><au>Jung, Yoon Seok</au><au>Lee, Ji-Min</au><au>Kim, Young-Hoon</au><au>Lee, Yong Soo</au><au>Kim, Jina</au><au>Dewidar, Bedair</au><au>Jeong, Won-Il</au><au>Lee, In-Kyu</au><au>Cho, Sung Jin</au><au>Dooley, Steven</au><au>Lee, Chul-Ho</au><au>Li, Xiaoying</au><au>Choi, Hueng-Sik</au><au>Villena, Josep A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Orphan nuclear receptor ERRγ is a key regulator of human fibrinogen gene expression</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-07-01</date><risdate>2017</risdate><volume>12</volume><issue>7</issue><spage>e0182141</spage><epage>e0182141</epage><pages>e0182141-e0182141</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Fibrinogen, 1 of 13 coagulation factors responsible for normal blood clotting, is synthesized by hepatocytes. Detailed roles of the orphan nuclear receptors regulating fibrinogen gene expression have not yet been fully elucidated. Here, we identified estrogen-related receptor gamma (ERRγ) as a novel transcriptional regulator of human fibrinogen gene expression. Overexpression of ERRγ specially increased fibrinogen expression in human hepatoma cell line. Cannabinoid receptor types 1(CB1R) agonist arachidonyl-2'-chloroethylamide (ACEA) up-regulated transcription of fibrinogen via induction of ERRγ, whereas knockdown of ERRγ attenuated fibrinogen expression. Deletion analyses of the fibrinogen γ (FGG) gene promoter and ChIP assays revealed binding sites of ERRγ on human fibrinogen γ gene promoter. Moreover, overexpression of ERRγ was sufficient to increase fibrinogen gene expression, whereas treatment with GSK5182, a selective inverse agonist of ERRγ led to its attenuation in cell culture. Finally, fibrinogen and ERRγ gene expression were elevated in liver tissue of obese patients suggesting a conservation of this mechanism. Overall, this study elucidates a molecular mechanism linking CB1R signaling, ERRγ expression and fibrinogen gene transcription. GSK5182 may have therapeutic potential to treat hyperfibrinogenemia.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28750085</pmid><doi>10.1371/journal.pone.0182141</doi><orcidid>https://orcid.org/0000-0002-3163-1572</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_2017529893 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult Aged Animals Binding sites Biology and Life Sciences Blood clots Blood coagulation Cannabinoid CB1 receptors Cell culture Clonal deletion Clotting Coagulation Conservation Diabetes Endocrinology Estrogens Fibrinogen Fibrinogen - genetics Fibrinogen - metabolism Gene deletion Gene expression Gene Expression Regulation Gene Knockdown Techniques Hep G2 Cells Hepatocytes Hepatoma Hospitals Humans Insulin Kinases Laboratories Ligands Liver Liver - metabolism Liver diseases Medicine Medicine and Health Sciences Metabolic disorders Mice Middle Aged Non-alcoholic Fatty Liver Disease - genetics Nuclear receptors Obesity Obesity - genetics Orphan nuclear receptors Phosphatase Promoter Regions, Genetic - genetics R&D Receptor, Cannabinoid, CB1 - metabolism Receptors Receptors, Estrogen - metabolism Research & development Research and Analysis Methods Rodents Signaling Transcription Transcription, Genetic |
| title | Orphan nuclear receptor ERRγ is a key regulator of human fibrinogen gene expression |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-30T19%3A39%3A39IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Orphan%20nuclear%20receptor%20ERR%CE%B3%20is%20a%20key%20regulator%20of%20human%20fibrinogen%20gene%20expression&rft.jtitle=PloS%20one&rft.au=Zhang,%20Yaochen&rft.date=2017-07-01&rft.volume=12&rft.issue=7&rft.spage=e0182141&rft.epage=e0182141&rft.pages=e0182141-e0182141&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0182141&rft_dat=%3Cproquest_plos_%3E1924604541%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2017529893&rft_id=info:pmid/28750085&rft_doaj_id=oai_doaj_org_article_c3c382e53cfa4ae596ea2013e77df67d&rfr_iscdi=true |