{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T04:01:45Z","timestamp":1792123305632,"version":"4.4.0"},"reference-count":47,"publisher":"American Society for Clinical Investigation","issue":"16","license":[{"start":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T00:00:00Z","timestamp":1629676800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["K01AA26385,R01 DK107682,R01 AA025208,U01 AA026917,UH2 AA026903"],"award-info":[{"award-number":["K01AA26385,R01 DK107682,R01 AA025208,U01 AA026917,UH2 AA026903"]}]},{"name":"Indiana University","award":["IU RSFG,the Ralph W."],"award-info":[{"award-number":["IU RSFG,the Ralph W."]}]},{"name":"Indiana University","award":["Grace M. Showalter Research Trust"],"award-info":[{"award-number":["Grace M. Showalter Research Trust"]}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"crossref","award":["1I01CX000361"],"award-info":[{"award-number":["1I01CX000361"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006975","name":"Indiana Clinical and Translational Sciences Institute","doi-asserted-by":"crossref","award":["UL1TR002529"],"award-info":[{"award-number":["UL1TR002529"]}],"id":[{"id":"10.13039\/100006975","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,8,23]]},"abstract":"<jats:p>\n                    Alcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid\n                    <jats:bold>\u03c9<\/jats:bold>\n                    -hydroxylation of medium- and long-chain fatty acid metabolized by the cytochrome P450 4A (CYP4A) family is an alternative pathway for fatty acid metabolism. The molecular mechanisms of CYP4A in ALD pathogenesis have not been elucidated. In this study, WT and\n                    <jats:italic>\n                      Shp\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice were fed with a modified ethanol-binge, National Institute on Alcohol Abuse and Alcoholism model (10 days of ethanol feeding plus single binge). Liver tissues were collected every 6 hours for 24 hours and analyzed using RNA-Seq. The effects of REV-ERB\n                    <jats:bold>\u03b1<\/jats:bold>\n                    agonist (SR9009, 100 mg\/kg\/d) or CYP4A antagonist (HET0016, 5 mg\/kg\/d) in ethanol-fed mice were also evaluated. We found that hepatic\n                    <jats:italic>Cyp4a10<\/jats:italic>\n                    and\n                    <jats:italic>Cyp4a14<\/jats:italic>\n                    expression were significantly upregulated in WT mice, but not in\n                    <jats:italic>\n                      Shp\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    <\/jats:italic>\n                    mice, fed with ethanol. ChIP quantitative PCR and promoter assay revealed that REV-ERB\n                    <jats:bold>\u03b1<\/jats:bold>\n                    is the transcriptional repressor of\n                    <jats:italic>Cyp4a10<\/jats:italic>\n                    and\n                    <jats:italic>Cyp4a14<\/jats:italic>\n                    .\n                    <jats:italic>Rev-Erb<\/jats:italic>\n                    <jats:bold>\u03b1<\/jats:bold>\n                    <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    hepatocytes had a marked induction of both\n                    <jats:italic>Cyp4a<\/jats:italic>\n                    genes and lipid accumulation. REV-ERB\n                    <jats:bold>\u03b1<\/jats:bold>\n                    agonist SR9009 or CYP4A antagonist HET0016 attenuated\n                    <jats:italic>Cyp4a<\/jats:italic>\n                    induction by ethanol and prevented alcohol-induced steatosis. Here, we have identified a role for the SHP\/REV-ERB\n                    <jats:bold>\u03b1<\/jats:bold>\n                    \/CYP4A axis in the pathogenesis of ALD. Our data also suggest REV-ERB\n                    <jats:bold>\u03b1<\/jats:bold>\n                    or CYP4A as the potential therapeutic targets for ALD.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.140687","type":"journal-article","created":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T16:37:37Z","timestamp":1629736657000},"source":"Crossref","is-referenced-by-count":26,"title":["The role of SHP\/REV-ERB\u03b1\/CYP4A axis in the pathogenesis of alcohol-associated liver disease"],"prefix":"10.1172","volume":"6","author":[{"given":"Zhihong","family":"Yang","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana V.","family":"Smalling","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanchao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Praveen","family":"Kusumanchi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Will","family":"Bogaert","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don A.","family":"Delker","sequence":"additional","affiliation":[{"name":"Divisions of Gastroenterology, University of Utah, Salt Lake City, Utah, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Skill","sequence":"additional","affiliation":[{"name":"Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen","family":"Han","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, 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