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This group has reported that \u03b14 nicotinic acetylcholine receptors (\u03b14 nAChRs) act as sensors for alcohol in lung cells. This study tested the hypothesis that \u03b14 nAChRs mediate the effects of alcohol in the liver.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Expression of acetylcholine receptor subunits in mouse liver was determined by RNA sequencing (RNA\u2010seq). \u03b14 nAChR knockout (\u03b14 KO) mice were generated in C57BL\/6J mice by introducing a mutation encoding an early stop codon in exon 4 of <jats:italic>Chrna4<\/jats:italic>, the gene encoding the \u03b14 subunit of the nAChR. The presence of the inactivating mutation was established by polymerase chain reaction and genomic sequencing, and the lack of \u03b14 nAChR function was confirmed in primary fibroblasts isolated from the \u03b14 KO mice. Wild\u2010type (WT) and \u03b14 KO mice were fed the Lieber\u2010DeCarli diet (with 36% of calories from alcohol) or pair fed an isocaloric maltose\u2010dextrin control diet for a 6\u2010week period that included a ramping up phase of increasing dietary alcohol.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Chrna4<\/jats:italic> was the most abundantly expressed nAChR subunit gene in mouse livers. After 6\u2009weeks of alcohol exposure, WT mice had elevated serum transaminases and their livers showed increased fat accumulation, decreased Sirt1 protein levels, and accumulation of markers of oxidative stress and inflammation including Cyp2E1, Nos2, Sod1, Slc7a11, TNF\u03b1, and PAI1. All these responses to alcohol were either absent or significantly attenuated in \u03b14 KO animals.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Together, these observations support the conclusion that activation of \u03b14 nAChRs by alcohol or one of its metabolites is one of the initial events promoting the accumulation of excess fat and expression of inflammatory mediators. Thus, \u03b14 nAChRs may represent viable targets for intervention in chronic alcohol\u2010related liver disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14893","type":"journal-article","created":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T10:16:48Z","timestamp":1655720208000},"page":"1371-1383","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mice lacking \u03b14 nicotinic acetylcholine receptors are protected against alcohol\u2010associated liver injury"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4381-1087","authenticated-orcid":false,"given":"Walter H.","family":"Watson","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine University of Louisville  Louisville Kentucky USA"},{"name":"Department of Pharmacology and Toxicology University of Louisville  Louisville Kentucky 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