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Orphan nuclear receptor ERRγ regulates hepatic TGF-β2 expression and fibrogenic response in CCl4-induced acute liver injury
Acute liver injury results from the complex interactions of various pathological processes. The TGF-β superfamily plays a crucial role in orchestrating fibrogenic response. In contrast to TGF-β1, a role of TGF-β2 in hepatic fibrogenic response has not been fully investigated. In this study, we showe...
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| Published in: | Archives of toxicology 2021-09, Vol.95 (9), p.3071-3084 |
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| creator | Jung, Yoon Seok Kim, Yong-Hoon Radhakrishnan, Kamalakannan Kim, Jina Lee, In-Kyu Cho, Sung Jin Kim, Don-Kyu Dooley, Steven Lee, Chul-Ho Choi, Hueng-Sik |
| description | Acute liver injury results from the complex interactions of various pathological processes. The TGF-β superfamily plays a crucial role in orchestrating fibrogenic response. In contrast to TGF-β1, a role of TGF-β2 in hepatic fibrogenic response has not been fully investigated. In this study, we showed that TGF-β2 gene expression and secretion are induced in the liver of CCl
4
(1 ml/kg)-treated WT mice. Studies with hepatocyte specific ERRγ knockout mice or treatment with an ERRγ-specific inverse agonist, GSK5182 (40 mg/kg), indicated that CCl
4
-induced hepatic TGF-β2 production is ERRγ dependent. Moreover, IL6 was found as upstream signal to induce hepatic ERRγ and TGF-β2 gene expression in CCl
4
-mediated acute toxicity model. Over-expression of ERRγ was sufficient to induce hepatic TGF-β2 expression, whereas ERRγ depletion markedly reduces IL6-induced TGF-β2 gene expression and secretion in vitro and in vivo. Promoter assays showed that ERRγ directly binds to an ERR response element in the TGF-β2 promoter to induce TGF-β2 transcription. Finally, GSK5182 diminished CCl
4
-induced fibrogenic response through inhibition of ERRγ-mediated TGF-β2 production. Taken together, these results firstly demonstrate that ERRγ can regulate the TGF-β2-mediated fibrogenic response in a mouse model of CC1
4
-induced acute liver injury. |
| doi_str_mv | 10.1007/s00204-021-03112-1 |
| format | article |
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4
(1 ml/kg)-treated WT mice. Studies with hepatocyte specific ERRγ knockout mice or treatment with an ERRγ-specific inverse agonist, GSK5182 (40 mg/kg), indicated that CCl
4
-induced hepatic TGF-β2 production is ERRγ dependent. Moreover, IL6 was found as upstream signal to induce hepatic ERRγ and TGF-β2 gene expression in CCl
4
-mediated acute toxicity model. Over-expression of ERRγ was sufficient to induce hepatic TGF-β2 expression, whereas ERRγ depletion markedly reduces IL6-induced TGF-β2 gene expression and secretion in vitro and in vivo. Promoter assays showed that ERRγ directly binds to an ERR response element in the TGF-β2 promoter to induce TGF-β2 transcription. Finally, GSK5182 diminished CCl
4
-induced fibrogenic response through inhibition of ERRγ-mediated TGF-β2 production. Taken together, these results firstly demonstrate that ERRγ can regulate the TGF-β2-mediated fibrogenic response in a mouse model of CC1
4
-induced acute liver injury.</description><identifier>ISSN: 0340-5761</identifier><identifier>EISSN: 1432-0738</identifier><identifier>DOI: 10.1007/s00204-021-03112-1</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Acute toxicity ; Biocompatibility ; Biomedical and Life Sciences ; Biomedicine ; Carbon tetrachloride ; Depletion ; Environmental Health ; Gene expression ; Injuries ; Interleukin 6 ; Inverse agonists ; Liver ; Molecular Toxicology ; Occupational Medicine/Industrial Medicine ; Overexpression ; Pharmacology/Toxicology ; Toxicity ; Transcription ; Transforming growth factor-b1</subject><ispartof>Archives of toxicology, 2021-09, Vol.95 (9), p.3071-3084</ispartof><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021</rights><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c352t-9dd7cbf000c6364b645ec549045197c67b12b021d8bcc4da2eafe8a7e7c3fb383</citedby><cites>FETCH-LOGICAL-c352t-9dd7cbf000c6364b645ec549045197c67b12b021d8bcc4da2eafe8a7e7c3fb383</cites><orcidid>0000-0002-3163-1572 ; 0000-0002-6996-5746</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></links><search><creatorcontrib>Jung, Yoon Seok</creatorcontrib><creatorcontrib>Kim, Yong-Hoon</creatorcontrib><creatorcontrib>Radhakrishnan, Kamalakannan</creatorcontrib><creatorcontrib>Kim, Jina</creatorcontrib><creatorcontrib>Lee, In-Kyu</creatorcontrib><creatorcontrib>Cho, Sung Jin</creatorcontrib><creatorcontrib>Kim, Don-Kyu</creatorcontrib><creatorcontrib>Dooley, Steven</creatorcontrib><creatorcontrib>Lee, Chul-Ho</creatorcontrib><creatorcontrib>Choi, Hueng-Sik</creatorcontrib><title>Orphan nuclear receptor ERRγ regulates hepatic TGF-β2 expression and fibrogenic response in CCl4-induced acute liver injury</title><title>Archives of toxicology</title><addtitle>Arch Toxicol</addtitle><description>Acute liver injury results from the complex interactions of various pathological processes. The TGF-β superfamily plays a crucial role in orchestrating fibrogenic response. In contrast to TGF-β1, a role of TGF-β2 in hepatic fibrogenic response has not been fully investigated. In this study, we showed that TGF-β2 gene expression and secretion are induced in the liver of CCl
4
(1 ml/kg)-treated WT mice. Studies with hepatocyte specific ERRγ knockout mice or treatment with an ERRγ-specific inverse agonist, GSK5182 (40 mg/kg), indicated that CCl
4
-induced hepatic TGF-β2 production is ERRγ dependent. Moreover, IL6 was found as upstream signal to induce hepatic ERRγ and TGF-β2 gene expression in CCl
4
-mediated acute toxicity model. Over-expression of ERRγ was sufficient to induce hepatic TGF-β2 expression, whereas ERRγ depletion markedly reduces IL6-induced TGF-β2 gene expression and secretion in vitro and in vivo. Promoter assays showed that ERRγ directly binds to an ERR response element in the TGF-β2 promoter to induce TGF-β2 transcription. Finally, GSK5182 diminished CCl
4
-induced fibrogenic response through inhibition of ERRγ-mediated TGF-β2 production. Taken together, these results firstly demonstrate that ERRγ can regulate the TGF-β2-mediated fibrogenic response in a mouse model of CC1
4
-induced acute liver injury.</description><subject>Acute toxicity</subject><subject>Biocompatibility</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Carbon tetrachloride</subject><subject>Depletion</subject><subject>Environmental Health</subject><subject>Gene expression</subject><subject>Injuries</subject><subject>Interleukin 6</subject><subject>Inverse agonists</subject><subject>Liver</subject><subject>Molecular Toxicology</subject><subject>Occupational Medicine/Industrial Medicine</subject><subject>Overexpression</subject><subject>Pharmacology/Toxicology</subject><subject>Toxicity</subject><subject>Transcription</subject><subject>Transforming growth factor-b1</subject><issn>0340-5761</issn><issn>1432-0738</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kM9KxDAQxoMouK6-gKeA5-jkT5vuURZdBWFhWc8hTadrl5rWpBU9-FL6Hj6T0RW8eRpm5vfNx3yEnHI45wD6IgIIUAwEZyA5F4zvkQlXUjDQstgnE5AKWKZzfkiOYtwCcFHM5IS8LUP_YD31o2vRBhrQYT90gV6tVp8fqd2MrR0w0gfs7dA4ul5cs893QfGlDxhj03lqfUXrpgzdBn0i0rjvfETaeDqft4o1vhodVtS6cUDaNs8Y0m47htdjclDbNuLJb52S--ur9fyG3S0Xt_PLO-ZkJgY2qyrtyhoAXC5zVeYqQ5epGaiMz7TLdclFmX6vitI5VVmBtsbCatRO1qUs5JSc7e72oXsaMQ5m243BJ0sjslwKkYlMJ0rsKBe6GAPWpg_Now2vhoP5jtnsYjbJyvzEbHgSyZ0oJthvMPyd_kf1BWHygpQ</recordid><startdate>20210901</startdate><enddate>20210901</enddate><creator>Jung, Yoon Seok</creator><creator>Kim, Yong-Hoon</creator><creator>Radhakrishnan, Kamalakannan</creator><creator>Kim, Jina</creator><creator>Lee, In-Kyu</creator><creator>Cho, Sung Jin</creator><creator>Kim, Don-Kyu</creator><creator>Dooley, Steven</creator><creator>Lee, Chul-Ho</creator><creator>Choi, Hueng-Sik</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T2</scope><scope>7TK</scope><scope>7U7</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>MBDVC</scope><scope>PATMY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PYCSY</scope><scope>Q9U</scope><orcidid>https://orcid.org/0000-0002-3163-1572</orcidid><orcidid>https://orcid.org/0000-0002-6996-5746</orcidid></search><sort><creationdate>20210901</creationdate><title>Orphan nuclear receptor ERRγ regulates hepatic TGF-β2 expression and fibrogenic response in CCl4-induced acute liver injury</title><author>Jung, Yoon Seok ; 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The TGF-β superfamily plays a crucial role in orchestrating fibrogenic response. In contrast to TGF-β1, a role of TGF-β2 in hepatic fibrogenic response has not been fully investigated. In this study, we showed that TGF-β2 gene expression and secretion are induced in the liver of CCl
4
(1 ml/kg)-treated WT mice. Studies with hepatocyte specific ERRγ knockout mice or treatment with an ERRγ-specific inverse agonist, GSK5182 (40 mg/kg), indicated that CCl
4
-induced hepatic TGF-β2 production is ERRγ dependent. Moreover, IL6 was found as upstream signal to induce hepatic ERRγ and TGF-β2 gene expression in CCl
4
-mediated acute toxicity model. Over-expression of ERRγ was sufficient to induce hepatic TGF-β2 expression, whereas ERRγ depletion markedly reduces IL6-induced TGF-β2 gene expression and secretion in vitro and in vivo. Promoter assays showed that ERRγ directly binds to an ERR response element in the TGF-β2 promoter to induce TGF-β2 transcription. Finally, GSK5182 diminished CCl
4
-induced fibrogenic response through inhibition of ERRγ-mediated TGF-β2 production. Taken together, these results firstly demonstrate that ERRγ can regulate the TGF-β2-mediated fibrogenic response in a mouse model of CC1
4
-induced acute liver injury.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><doi>10.1007/s00204-021-03112-1</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-3163-1572</orcidid><orcidid>https://orcid.org/0000-0002-6996-5746</orcidid></addata></record> |
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| source | Springer Nature |
| subjects | Acute toxicity Biocompatibility Biomedical and Life Sciences Biomedicine Carbon tetrachloride Depletion Environmental Health Gene expression Injuries Interleukin 6 Inverse agonists Liver Molecular Toxicology Occupational Medicine/Industrial Medicine Overexpression Pharmacology/Toxicology Toxicity Transcription Transforming growth factor-b1 |
| title | Orphan nuclear receptor ERRγ regulates hepatic TGF-β2 expression and fibrogenic response in CCl4-induced acute liver injury |
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