Estrogen and Estrogen Receptor-α-Mediated Transrepression of Bile Salt Export Pump
Among diseases unique to pregnancy, intrahepatic cholestasis of pregnancy is the most prevalent disorder with elevated serum bile acid levels. We have previously shown that estrogen 17β-estradiol (E2) transrepresses bile salt export pump (BSEP) through an interaction between estrogen receptor (ER)-α...
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| Veröffentlicht in: | Molecular endocrinology (Baltimore, Md.) Md.), 2015-04, Vol.29 (4), p.613-626 |
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| container_title | Molecular endocrinology (Baltimore, Md.) |
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| creator | Chen, Yuan Vasilenko, Alex Song, Xiulong Valanejad, Leila Verma, Ruchi You, Sangmin Yan, Bingfang Shiffka, Stephanie Hargreaves, Leeza Nadolny, Christina Deng, Ruitang |
| description | Among diseases unique to pregnancy, intrahepatic cholestasis of pregnancy is the most prevalent disorder with elevated serum bile acid levels. We have previously shown that estrogen 17β-estradiol (E2) transrepresses bile salt export pump (BSEP) through an interaction between estrogen receptor (ER)-α and farnesoid X receptor (FXR) and transrepression of BSEP by E2/ERα is an etiological contributing factor to intrahepatic cholestasis of pregnancy. Currently the mechanistic insights into such transrepression are not fully understood. In this study, the dynamics of coregulator recruitment to BSEP promoter after FXR activation and E2 treatment were established with quantitative chromatin immunoprecipitation assays. Coactivator peroxisome proliferator-activated receptor-γ coactivator-1 was predominantly recruited to the BSEP promoter upon FXR activation, and its recruitment was decreased by E2 treatment. Meanwhile, recruitment of nuclear receptor corepressor was markedly increased upon E2 treatment. Functional evaluation of ERα and ERβ chimeras revealed that domains AC of ERα are the determinants for ERα-specific transrepression on BSEP. Further studies with various truncated ERα proteins identified the domains in ERα responsible for ligand-dependent and ligand-independent transrepression. Truncated ERα-AD exhibited potent ligand-independent transrepressive activity, whereas ERα-CF was fully capable of transrepressing BSEP ligand dependently in vitro in Huh 7 cells and in vivo in mice. Both ERα-AD and ERα-CF proteins were associated with FXR in the coimmunoprecipitation assays. In conclusion, E2 repressed BSEP expression through diminishing peroxisome proliferator-activated receptor-γ coactivator-1 recruitment with a concurrent increase in nuclear receptor corepressor recruitment to the BSEP promoter. Domains AD and CF in ERα mediated ligand-independent and ligand-dependent transrepression on BSEP, respectively, through interacting with FXR. |
| doi_str_mv | 10.1210/me.2015-1014 |
| format | Article |
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We have previously shown that estrogen 17β-estradiol (E2) transrepresses bile salt export pump (BSEP) through an interaction between estrogen receptor (ER)-α and farnesoid X receptor (FXR) and transrepression of BSEP by E2/ERα is an etiological contributing factor to intrahepatic cholestasis of pregnancy. Currently the mechanistic insights into such transrepression are not fully understood. In this study, the dynamics of coregulator recruitment to BSEP promoter after FXR activation and E2 treatment were established with quantitative chromatin immunoprecipitation assays. Coactivator peroxisome proliferator-activated receptor-γ coactivator-1 was predominantly recruited to the BSEP promoter upon FXR activation, and its recruitment was decreased by E2 treatment. Meanwhile, recruitment of nuclear receptor corepressor was markedly increased upon E2 treatment. Functional evaluation of ERα and ERβ chimeras revealed that domains AC of ERα are the determinants for ERα-specific transrepression on BSEP. Further studies with various truncated ERα proteins identified the domains in ERα responsible for ligand-dependent and ligand-independent transrepression. Truncated ERα-AD exhibited potent ligand-independent transrepressive activity, whereas ERα-CF was fully capable of transrepressing BSEP ligand dependently in vitro in Huh 7 cells and in vivo in mice. Both ERα-AD and ERα-CF proteins were associated with FXR in the coimmunoprecipitation assays. In conclusion, E2 repressed BSEP expression through diminishing peroxisome proliferator-activated receptor-γ coactivator-1 recruitment with a concurrent increase in nuclear receptor corepressor recruitment to the BSEP promoter. Domains AD and CF in ERα mediated ligand-independent and ligand-dependent transrepression on BSEP, respectively, through interacting with FXR.</description><identifier>ISSN: 0888-8809</identifier><identifier>EISSN: 1944-9917</identifier><identifier>DOI: 10.1210/me.2015-1014</identifier><identifier>PMID: 25675114</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Animals ; ATP Binding Cassette Subfamily B Member 11 ; ATP-Binding Cassette Transporters - genetics ; ATP-Binding Cassette Transporters - metabolism ; Cell Line, Tumor ; Estradiol - pharmacology ; Estrogen Receptor alpha - genetics ; Estrogen Receptor alpha - metabolism ; Humans ; Mice ; Original Research ; Promoter Regions, Genetic ; Receptors, Cytoplasmic and Nuclear - genetics ; Receptors, Cytoplasmic and Nuclear - metabolism ; Transcription Factors - genetics ; Transcription Factors - metabolism</subject><ispartof>Molecular endocrinology (Baltimore, Md.), 2015-04, Vol.29 (4), p.613-626</ispartof><rights>Copyright © 2015 by the Endocrine Society</rights><rights>Copyright © 2015 by the Endocrine Society 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c460t-2367d95a058a1a854cf0c674b77f94126432c3cff4b625f82ab105c4bdfc27fe3</citedby><cites>FETCH-LOGICAL-c460t-2367d95a058a1a854cf0c674b77f94126432c3cff4b625f82ab105c4bdfc27fe3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25675114$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Yuan</creatorcontrib><creatorcontrib>Vasilenko, Alex</creatorcontrib><creatorcontrib>Song, Xiulong</creatorcontrib><creatorcontrib>Valanejad, Leila</creatorcontrib><creatorcontrib>Verma, Ruchi</creatorcontrib><creatorcontrib>You, Sangmin</creatorcontrib><creatorcontrib>Yan, Bingfang</creatorcontrib><creatorcontrib>Shiffka, Stephanie</creatorcontrib><creatorcontrib>Hargreaves, Leeza</creatorcontrib><creatorcontrib>Nadolny, Christina</creatorcontrib><creatorcontrib>Deng, Ruitang</creatorcontrib><title>Estrogen and Estrogen Receptor-α-Mediated Transrepression of Bile Salt Export Pump</title><title>Molecular endocrinology (Baltimore, Md.)</title><addtitle>Mol Endocrinol</addtitle><description>Among diseases unique to pregnancy, intrahepatic cholestasis of pregnancy is the most prevalent disorder with elevated serum bile acid levels. We have previously shown that estrogen 17β-estradiol (E2) transrepresses bile salt export pump (BSEP) through an interaction between estrogen receptor (ER)-α and farnesoid X receptor (FXR) and transrepression of BSEP by E2/ERα is an etiological contributing factor to intrahepatic cholestasis of pregnancy. Currently the mechanistic insights into such transrepression are not fully understood. In this study, the dynamics of coregulator recruitment to BSEP promoter after FXR activation and E2 treatment were established with quantitative chromatin immunoprecipitation assays. Coactivator peroxisome proliferator-activated receptor-γ coactivator-1 was predominantly recruited to the BSEP promoter upon FXR activation, and its recruitment was decreased by E2 treatment. Meanwhile, recruitment of nuclear receptor corepressor was markedly increased upon E2 treatment. Functional evaluation of ERα and ERβ chimeras revealed that domains AC of ERα are the determinants for ERα-specific transrepression on BSEP. Further studies with various truncated ERα proteins identified the domains in ERα responsible for ligand-dependent and ligand-independent transrepression. Truncated ERα-AD exhibited potent ligand-independent transrepressive activity, whereas ERα-CF was fully capable of transrepressing BSEP ligand dependently in vitro in Huh 7 cells and in vivo in mice. Both ERα-AD and ERα-CF proteins were associated with FXR in the coimmunoprecipitation assays. In conclusion, E2 repressed BSEP expression through diminishing peroxisome proliferator-activated receptor-γ coactivator-1 recruitment with a concurrent increase in nuclear receptor corepressor recruitment to the BSEP promoter. Domains AD and CF in ERα mediated ligand-independent and ligand-dependent transrepression on BSEP, respectively, through interacting with FXR.</description><subject>Animals</subject><subject>ATP Binding Cassette Subfamily B Member 11</subject><subject>ATP-Binding Cassette Transporters - genetics</subject><subject>ATP-Binding Cassette Transporters - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Estradiol - pharmacology</subject><subject>Estrogen Receptor alpha - genetics</subject><subject>Estrogen Receptor alpha - metabolism</subject><subject>Humans</subject><subject>Mice</subject><subject>Original Research</subject><subject>Promoter Regions, Genetic</subject><subject>Receptors, Cytoplasmic and Nuclear - genetics</subject><subject>Receptors, Cytoplasmic and Nuclear - metabolism</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><issn>0888-8809</issn><issn>1944-9917</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kcFu1DAURa2Kig6FXdcoO1jg1nZsx9lUKtVAKxUV0bK2HOe5pErs1E4QfBY_wjfhUaYjKsHKevLRfU_nInREyTFllJwMcMwIFZgSyvfQitac47qm1TO0IkoprBSpD9CLlO5JJoSiz9EBE7ISlPIVulmnKYY78IXxbbEbvoCFcQoR__6FP0HbmQna4jYanyKMEVLqgi-CK953PRQ3pp-K9Y8xxKn4PA_jS7TvTJ_g1fY9RF8_rG_PL_DV9cfL87MrbLkkE2alrNpaGCKUoUYJbh2xsuJNVbmaUyZ5yWxpneONZMIpZhpKhOVN6yyrHJSH6HTJHedmgNaCn6Lp9Ri7wcSfOphOP_3x3Td9F75rXtY1q2QOeLsNiOFhhjTpoUsW-t54CHPSVMpsU2VnGX23oDaGlCW43RpK9KYHPYDe9KA3PWT89d-n7eBH8Rl4swBhHv8XhbdR5UKCb4ONnV8K0Pdhjj7r_fcBfwCvU6In</recordid><startdate>20150401</startdate><enddate>20150401</enddate><creator>Chen, Yuan</creator><creator>Vasilenko, Alex</creator><creator>Song, Xiulong</creator><creator>Valanejad, Leila</creator><creator>Verma, Ruchi</creator><creator>You, Sangmin</creator><creator>Yan, Bingfang</creator><creator>Shiffka, Stephanie</creator><creator>Hargreaves, Leeza</creator><creator>Nadolny, Christina</creator><creator>Deng, Ruitang</creator><general>Endocrine Society</general><general>Oxford University Press</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150401</creationdate><title>Estrogen and Estrogen Receptor-α-Mediated Transrepression of Bile Salt Export Pump</title><author>Chen, Yuan ; Vasilenko, Alex ; Song, Xiulong ; Valanejad, Leila ; Verma, Ruchi ; You, Sangmin ; Yan, Bingfang ; Shiffka, Stephanie ; Hargreaves, Leeza ; Nadolny, Christina ; Deng, Ruitang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c460t-2367d95a058a1a854cf0c674b77f94126432c3cff4b625f82ab105c4bdfc27fe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>ATP Binding Cassette Subfamily B Member 11</topic><topic>ATP-Binding Cassette Transporters - genetics</topic><topic>ATP-Binding Cassette Transporters - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Estradiol - pharmacology</topic><topic>Estrogen Receptor alpha - genetics</topic><topic>Estrogen Receptor alpha - metabolism</topic><topic>Humans</topic><topic>Mice</topic><topic>Original Research</topic><topic>Promoter Regions, Genetic</topic><topic>Receptors, Cytoplasmic and Nuclear - genetics</topic><topic>Receptors, Cytoplasmic and Nuclear - metabolism</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Yuan</creatorcontrib><creatorcontrib>Vasilenko, Alex</creatorcontrib><creatorcontrib>Song, Xiulong</creatorcontrib><creatorcontrib>Valanejad, Leila</creatorcontrib><creatorcontrib>Verma, Ruchi</creatorcontrib><creatorcontrib>You, Sangmin</creatorcontrib><creatorcontrib>Yan, Bingfang</creatorcontrib><creatorcontrib>Shiffka, Stephanie</creatorcontrib><creatorcontrib>Hargreaves, Leeza</creatorcontrib><creatorcontrib>Nadolny, Christina</creatorcontrib><creatorcontrib>Deng, Ruitang</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Yuan</au><au>Vasilenko, Alex</au><au>Song, Xiulong</au><au>Valanejad, Leila</au><au>Verma, Ruchi</au><au>You, Sangmin</au><au>Yan, Bingfang</au><au>Shiffka, Stephanie</au><au>Hargreaves, Leeza</au><au>Nadolny, Christina</au><au>Deng, Ruitang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Estrogen and Estrogen Receptor-α-Mediated Transrepression of Bile Salt Export Pump</atitle><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle><addtitle>Mol Endocrinol</addtitle><date>2015-04-01</date><risdate>2015</risdate><volume>29</volume><issue>4</issue><spage>613</spage><epage>626</epage><pages>613-626</pages><issn>0888-8809</issn><eissn>1944-9917</eissn><abstract>Among diseases unique to pregnancy, intrahepatic cholestasis of pregnancy is the most prevalent disorder with elevated serum bile acid levels. We have previously shown that estrogen 17β-estradiol (E2) transrepresses bile salt export pump (BSEP) through an interaction between estrogen receptor (ER)-α and farnesoid X receptor (FXR) and transrepression of BSEP by E2/ERα is an etiological contributing factor to intrahepatic cholestasis of pregnancy. Currently the mechanistic insights into such transrepression are not fully understood. In this study, the dynamics of coregulator recruitment to BSEP promoter after FXR activation and E2 treatment were established with quantitative chromatin immunoprecipitation assays. Coactivator peroxisome proliferator-activated receptor-γ coactivator-1 was predominantly recruited to the BSEP promoter upon FXR activation, and its recruitment was decreased by E2 treatment. Meanwhile, recruitment of nuclear receptor corepressor was markedly increased upon E2 treatment. Functional evaluation of ERα and ERβ chimeras revealed that domains AC of ERα are the determinants for ERα-specific transrepression on BSEP. Further studies with various truncated ERα proteins identified the domains in ERα responsible for ligand-dependent and ligand-independent transrepression. Truncated ERα-AD exhibited potent ligand-independent transrepressive activity, whereas ERα-CF was fully capable of transrepressing BSEP ligand dependently in vitro in Huh 7 cells and in vivo in mice. Both ERα-AD and ERα-CF proteins were associated with FXR in the coimmunoprecipitation assays. In conclusion, E2 repressed BSEP expression through diminishing peroxisome proliferator-activated receptor-γ coactivator-1 recruitment with a concurrent increase in nuclear receptor corepressor recruitment to the BSEP promoter. Domains AD and CF in ERα mediated ligand-independent and ligand-dependent transrepression on BSEP, respectively, through interacting with FXR.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>25675114</pmid><doi>10.1210/me.2015-1014</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | Journals@Ovid Ovid Autoload; Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals ATP Binding Cassette Subfamily B Member 11 ATP-Binding Cassette Transporters - genetics ATP-Binding Cassette Transporters - metabolism Cell Line, Tumor Estradiol - pharmacology Estrogen Receptor alpha - genetics Estrogen Receptor alpha - metabolism Humans Mice Original Research Promoter Regions, Genetic Receptors, Cytoplasmic and Nuclear - genetics Receptors, Cytoplasmic and Nuclear - metabolism Transcription Factors - genetics Transcription Factors - metabolism |
| title | Estrogen and Estrogen Receptor-α-Mediated Transrepression of Bile Salt Export Pump |
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