{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:35:32Z","timestamp":1792650932996,"version":"4.5.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:p>\n                    Alcohol\u2010associated liver disease (ALD) is a major cause of alcohol\u2010related mortality. Sex differences in sensitivity to ALD are well described, but these are often disregarded in studies of ALD development. We aimed to define sex\u2010specific pathways in liver exposed to alcohol. Mice were fed the Lieber\u2010DeCarli alcohol liquid diet or a combination of a high\u2010fat diet with alcohol in water. Single\u2010cell RNA sequencing (scRNA\u2010Seq) was performed on liver cells from male and female mice. Mice were treated with adeno\u2010associated virus (AAV)\u2010short hairpin (sh)Control or AAV\u2010sh lysine demethylase 5b (shKdm5b) and\/or AAV\u2010shKdm5c vectors. Changes after Kdm5b\/5c knockdown were assessed by RNA\u2010Seq and histone H3 lysine K4 (H3K4)me3 chromatin immunoprecipitation\u2010Seq analysis. Using scRNA\u2010Seq analysis, we found several sex\u2010specific pathways induced by alcohol, including pathways related to lipid metabolism and hepatocyte differentiation. Bioinformatic analysis suggested that two epigenetic regulators, H3K4\u2010specific lysine demethylases KDM5B and KDM5C, contribute to sex differences in alcohol effects. We found that in alcohol\u2010fed male mice, KDM5B and KDM5C are involved in hepatocyte nuclear factor 4 alpha (\n                    <jats:italic toggle=\"yes\">Hnf4a<\/jats:italic>\n                    ) down\u2010regulation, hepatocyte dedifferentiation, and an increase in fatty acid synthesis. This effect is mediated by alcohol\u2010induced KDM5B and KDM5C recruitment to\n                    <jats:italic toggle=\"yes\">Hnf4a<\/jats:italic>\n                    and other gene promoters in male but not in female mice.\n                    <jats:italic toggle=\"yes\">Kdm5b<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">Kdm5c<\/jats:italic>\n                    knockdown or KDM5\u2010inhibitor treatment prevented alcohol\u2010induced lipid accumulation and restored levels of\n                    <jats:italic toggle=\"yes\">Hnf4a<\/jats:italic>\n                    and other hepatocyte differentiation genes in male mice. In addition,\n                    <jats:italic toggle=\"yes\">Kdm5b<\/jats:italic>\n                    knockdown prevented hepatocellular carcinoma development in male mice by up\u2010regulating\n                    <jats:italic toggle=\"yes\">Hnf4a<\/jats:italic>\n                    and decreasing tumor cell proliferation.\n                    <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>\n                    Alcohol specifically activates KDM5 demethylases in male mice to promote alcohol\u2010induced hepatocyte dedifferentiation and tumor development.\n                  <\/jats:p>","DOI":"10.1002\/hep4.1895","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T11:28:23Z","timestamp":1643282903000},"page":"1373-1391","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":20,"title":["Male\u2010Specific Activation of Lysine Demethylases 5B and 5C Mediates Alcohol\u2010Induced Liver Injury and Hepatocyte Dedifferentiation"],"prefix":"10.1097","volume":"6","author":[{"given":"Michael","family":"Schonfeld","sequence":"first","affiliation":[{"name":"Department of Internal Medicine,University of Kansas Medical Center,Kansas City,KS,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice","family":"Averilla","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Kansas Medical Center,Kansas City,KS,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumedha","family":"Gunewardena","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology,University of Kansas Medical Center,Kansas City,KS,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven A.","family":"Weinman","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Kansas Medical Center,Kansas City,KS,USA"},{"name":"Liver Center,University of Kansas Medical Center,Kansas City,KS,USA"},{"name":"Kansas City VA Medical Center,Kansas City,MO,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Tikhanovich","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,University of Kansas Medical Center,Kansas City,KS,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"hep41895-bib-0001-20251121","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1155\/2015\/814827","article-title":"Risk factors for mortality in patients with alcoholic hepatitis and assessment of prognostic models: a population\u2010based study","volume":"29","year":"2015","journal-title":"Can J Gastroenterol Hepatol"},{"key":"hep41895-bib-0002-20251121","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.neuroscience.2019.10.013","article-title":"CCL2\/CCR2 chemokine system in embryonic hypothalamus: involvement in sexually dimorphic stimulatory effects of prenatal ethanol exposure on peptide\u2010expressing neurons","volume":"424","year":"2020","journal-title":"Neuroscience"},{"key":"hep41895-bib-0003-20251121","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/0016-5085(87)90240-X","article-title":"Androgen\u2010responsive functions of male rat liver. 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