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Based on these findings, we hypothesized that hepatocyte\u2010specific \u03b14 nAChRs may directly contribute to the detrimental effects of alcohol on the liver.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Hepatocyte\u2010specific \u03b14 knockout mice (\u03b14HepKO) were generated, and the absence of \u03b14 nAChR was confirmed through PCR of genomic DNA. Female WT and \u03b14HepKO mice were exposed to alcohol in the NIAAA chronic\u2009+\u2009binge model. After 10\u2009days on the Lieber\u2013DeCarli liquid diet containing 5% (vol\/vol) alcohol or isocaloric maltose\u2010dextrin, the mice were gavaged with a single dose of alcohol or isocaloric maltose\u2010dextrin. The mice were euthanized 9\u2009h later and their organs harvested. Additionally, hepatocytes were isolated from WT, \u03b14HepKO, \u03b14floxed, and \u03b14KO mice and exposed to 80\u2009mM alcohol in\u00a0vitro for 24\u2009h. Steatosis, inflammation, and cell injury were assessed in both liver and isolated hepatocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In WT mice, alcohol exposure resulted in hepatic steatosis, inflammation, and injury as evidenced by increased liver triglycerides, neutrophil infiltration, and serum concentrations of liver enzymes. All of these responses were markedly lower in \u03b14HepKO mice. mRNA expression of genes involved in lipogenesis (<jats:italic>Srebf1<\/jats:italic>, <jats:italic>Fasn<\/jats:italic>, and <jats:italic>Dgat2<\/jats:italic>) and inflammation (<jats:italic>TNF\u03b1<\/jats:italic>, <jats:italic>Cxcl5<\/jats:italic>, <jats:italic>Cxcl1<\/jats:italic>, and <jats:italic>Serpine1<\/jats:italic>) were increased in the livers of WT mice exposed to alcohol in\u00a0vivo and in WT hepatocytes exposed to alcohol in\u00a0vitro. These changes were not observed in liver or hepatocytes from mice lacking \u03b14 nAChRs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>\u03b14 nAChRs expressed in hepatocytes mediate alcohol\u2010associated hepatoxicity. Therefore, the development of therapeutic strategies targeting hepatocyte \u03b14\u2010containing nAChRs could help reduce the burden of ALD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.15533","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T03:29:09Z","timestamp":1737689349000},"page":"515-525","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Alcohol\u2010induced liver injury is mediated via \u03b14\u2010containing nicotinic acetylcholine receptors expressed in hepatocytes"],"prefix":"10.1111","volume":"49","author":[{"given":"Jeffrey D.","family":"Ritzenthaler","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy and Critical Care Medicine and the Jane &amp; Leonard Korman Respiratory Institute Thomas Jefferson University  Philadelphia Pennsylvania 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