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Activation of IRF3 by viral infection in vivo greatly enhances bile acid\u2013 and aspirin-induced hepatotoxicity. Our results provide a critical link between the innate immune response and host metabolism, identifying IRF3-mediated down-regulation of RXR\u03b1 as a molecular mechanism for pathogen-associated metabolic diseases.<\/jats:p>","DOI":"10.1084\/jem.20060929","type":"journal-article","created":{"date-parts":[[2006,10,31]],"date-time":"2006-10-31T01:39:29Z","timestamp":1162258769000},"page":"2589-2602","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":34,"title":["A role for IRF3-dependent RXR\u03b1 repression in hepatotoxicity associated with viral infections"],"prefix":"10.1084","volume":"203","author":[{"given":"Edward K.","family":"Chow","sequence":"first","affiliation":[{"name":"1Molecular Biology Institute"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Castrillo","sequence":"additional","affiliation":[{"name":"2Howard Hughes Medical Institute"},{"name":"3Department of Pathology and Laboratory Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arash","family":"Shahangian","sequence":"additional","affiliation":[{"name":"4Department of Microbiology, Immunology, and Molecular Genetics"},{"name":"7Medical Scientist Training Program, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liming","family":"Pei","sequence":"additional","affiliation":[{"name":"2Howard Hughes Medical Institute"},{"name":"3Department of Pathology and Laboratory Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan M.","family":"O'Connell","sequence":"additional","affiliation":[{"name":"4Department of Microbiology, Immunology, and Molecular Genetics"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert L.","family":"Modlin","sequence":"additional","affiliation":[{"name":"4Department of Microbiology, Immunology, and Molecular Genetics"},{"name":"5Division of Dermatology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Tontonoz","sequence":"additional","affiliation":[{"name":"2Howard Hughes Medical Institute"},{"name":"3Department of Pathology and Laboratory Medicine"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Genhong","family":"Cheng","sequence":"additional","affiliation":[{"name":"1Molecular Biology Institute"},{"name":"4Department of Microbiology, Immunology, and Molecular Genetics"},{"name":"6Jonsson Comprehensive Cancer Center,"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[2006,10,30]]},"reference":[{"key":"2023072515243529200_BIB1","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1161\/01.CIR.102.7.779","volume":"102","year":"2000","journal-title":"Circulation."},{"key":"2023072515243529200_BIB2","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.2105\/AJPH.66.11.1096","volume":"66","year":"1976","journal-title":"Am. 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Pathol."},{"key":"2023072515243529200_BIB52","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1016\/0006-2952(87)90513-2","volume":"36","year":"1987","journal-title":"Biochem. Pharmacol."},{"key":"2023072515243529200_BIB53","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/S0090-9556(24)14906-9","volume":"27","year":"1999","journal-title":"Drug Metab. Dispos."},{"key":"2023072515243529200_BIB54","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1046\/j.1365-2362.2003.01154.x","volume":"33","year":"2003","journal-title":"Eur. J. Clin. Invest."},{"key":"2023072515243529200_BIB55","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1124\/dmd.105.005652","volume":"34","year":"2006","journal-title":"Drug Metab. Dispos."},{"key":"2023072515243529200_BIB56","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1006\/taap.1997.8313","volume":"147","year":"1997","journal-title":"Toxicol. Appl. 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