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An inverse agonist of estrogen-related receptor γ regulates 2-arachidonoylglycerol synthesis by modulating diacylglycerol lipase expression in alcohol-intoxicated miceoa mark
  • Jung, Yoon Seok ;
  • Kim, Yong Hoon ;
  • Radhakrishnan, Kamalakannan ;
  • kim, Jina ;
  • Kim, Don Kyu ;
  • Lee, Ji Hyeok ;
  • Oh, Hyunhee ;
  • Lee, In Kyu ;
  • Kim, Wook ;
  • Cho, Sung Jin ;
  • Choi, Cheol Soo ;
  • Dooley, Steven ;
  • Egan, Josephine M. ;
  • Lee, Chul Ho ;
  • Choi, Hueng Sik
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dc.contributor.authorJung, Yoon Seok-
dc.contributor.authorKim, Yong Hoon-
dc.contributor.authorRadhakrishnan, Kamalakannan-
dc.contributor.authorkim, Jina-
dc.contributor.authorKim, Don Kyu-
dc.contributor.authorLee, Ji Hyeok-
dc.contributor.authorOh, Hyunhee-
dc.contributor.authorLee, In Kyu-
dc.contributor.authorKim, Wook-
dc.contributor.authorCho, Sung Jin-
dc.contributor.authorChoi, Cheol Soo-
dc.contributor.authorDooley, Steven-
dc.contributor.authorEgan, Josephine M.-
dc.contributor.authorLee, Chul Ho-
dc.contributor.authorChoi, Hueng Sik-
dc.date.issued2020-02-01-
dc.identifier.issn1432-0738-
dc.identifier.urihttps://aurora.ajou.ac.kr/handle/2018.oak/31090-
dc.identifier.urihttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85077616241&origin=inward-
dc.description.abstractChronic alcohol feeding increases the levels of 2-arachidonoylglycerol (2-AG) in the liver, which activates hepatic cannabinoid receptor type 1 (CB1R), leading to oxidative liver injury. 2-AG biosynthesis is catalyzed by diacylglycerol lipase (DAGL). However, the mechanisms regulating hepatic DAGL gene expression and 2-AG production are largely unknown. In this study, we show that CB1R-induced estrogen-related receptor γ (ERRγ) controls hepatic DAGL gene expression and 2-AG levels. Arachidonyl-2′-chloroethylamide (ACEA), a synthetic CB1R agonist, significantly upregulated ERRγ, DAGLα, and DAGLβ, and increased 2-AG levels in the liver (10 mg/kg) and hepatocytes (10 μM) of wild-type (WT) mice. ERRγ overexpression upregulated DAGLα and DAGLβ expressions and increased 2-AG levels, whereas ERRγ knockdown abolished ACEA-induced DAGLα, DAGLβ, and 2-AG in vitro and in vivo. Promoter assays showed that ERRγ positively regulated DAGLα and DAGLβ transcription by binding to the ERR response element in the DAGLα and DAGLβ promoters. Chronic alcohol feeding (27.5% of total calories) induced hepatic steatosis and upregulated ERRγ, leading to increased DAGLα, DAGLβ, or 2-AG in WT mice, whereas these alcohol-induced effects did not occur in hepatocyte-specific CB1R knockout mice or in those treated with the ERRγ inverse agonist GSK5182 (40 mg/kg in mice and 10 μM in vitro). Taken together, these results indicate that suppression of alcohol-induced DAGLα and DAGLβ gene expressions and 2-AG levels by an ERRγ-specific inverse agonist may be a novel and attractive therapeutic approach for the treatment of alcoholic liver disease.-
dc.description.sponsorshipThis research was supported by the National Creative Research Initiatives Grant (20110018305) and Basic Science Research Program (NRF-2015R1C1A1A01051513) through the National Research Foundation of Korea (NRF) funded by the Korean government (Ministry of Science and ICT). This work was also supported by the KRIBB Research Initiative Program of the Republic of Korea. C.S.C. was supported by Korea Mouse Phenotyping Project (NRF-2014M3A9D5A01073886) of the Ministry of Science, ICT and Future Planning through the National Research Foundation. This research was supported by a Grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI16C1501). This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (Grant number: NRF-2017R1A2B3006406) and the Cooperative Research Program for Agriculture Science and Technology Development (No. PJ01280701) funded by Rural Development Administration, Republic of Korea.-
dc.description.sponsorshipThis research was supported by the National Creative Research Initiatives Grant (20110018305) and Basic Science Research Program (NRF-2015R1C1A1A01051513) through the National Research Foundation of Korea (NRF) funded by the Korean government (Ministry of Science and ICT). This work was also supported by the KRIBB Research Initiative Program of the Republic of Korea. C.S.C. was supported by Korea Mouse Phenotyping Project (NRF-2014M3A9D5A01073886) of the Ministry of Science, ICT and Future Planning through the National Research Foundation. This research was supported by a Grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare, Republic of Korea (Grant number: HI16C1501). This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (Grant number: NRF-2017R1A2B3006406) and the Cooperative Research Program for Agriculture Science and Technology Development (No. PJ01280701) funded by Rural Development Administration, Republic of Korea.-
dc.language.isoeng-
dc.publisherSpringer-
dc.subject.meshAnimals-
dc.subject.meshArachidonic Acids-
dc.subject.meshEndocannabinoids-
dc.subject.meshEthanol-
dc.subject.meshGene Expression Regulation-
dc.subject.meshGlycerides-
dc.subject.meshHep G2 Cells-
dc.subject.meshHepatocytes-
dc.subject.meshHumans-
dc.subject.meshLipoprotein Lipase-
dc.subject.meshLiver-
dc.subject.meshMale-
dc.subject.meshMice, Inbred C57BL-
dc.subject.meshMice, Knockout-
dc.subject.meshReceptor, Cannabinoid, CB1-
dc.subject.meshReceptors, Estrogen-
dc.subject.meshTamoxifen-
dc.titleAn inverse agonist of estrogen-related receptor γ regulates 2-arachidonoylglycerol synthesis by modulating diacylglycerol lipase expression in alcohol-intoxicated mice-
dc.typeArticle-
dc.citation.endPage438-
dc.citation.number2-
dc.citation.startPage427-
dc.citation.titleArchives of Toxicology-
dc.citation.volume94-
dc.identifier.bibliographicCitationArchives of Toxicology, Vol.94 No.2, pp.427-438-
dc.identifier.doi10.1007/s00204-019-02648-7-
dc.identifier.pmid31912162-
dc.identifier.scopusid2-s2.0-85077616241-
dc.identifier.urllink.springer.de/link/service/journals/00204/index.htm-
dc.subject.keyword2-AG-
dc.subject.keywordDAGL-
dc.subject.keywordEndocannabinoid-
dc.subject.keywordERRγ-
dc.subject.keywordGSK5182-
dc.subject.keywordHepatic CB1R-
dc.type.otherArticle-
dc.identifier.pissn0340-5761-
dc.description.isoatrue-
dc.subject.subareaToxicology-
dc.subject.subareaHealth, Toxicology and Mutagenesis-
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