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In this study, we observed YAP activation in patients with alcoholic steatosis, hepatitis, and cirrhosis. Accumulation of this protein in the nucleus was also observed in murine livers that were damaged after chronic\u2010plus\u2010single binge or moderate ethanol ingestion combined with carbon tetrachloride intoxication (ethanol\/CCl\n                    <jats:sub>4<\/jats:sub>\n                    ). To understand the role of this transcriptional coactivator in alcohol\u2010related liver injury, we knocked out the\n                    <jats:italic>Yap1<\/jats:italic>\n                    \u00a0gene in hepatocytes of floxed homozygotes through adeno\u2010associated virus (AAV8)\u2010mediated deletion utilizing Cre recombinase.\n                    <jats:italic>Yap1<\/jats:italic>\n                    \u00a0hepatocyte\u2010specific knockouts (KO) exhibited hemorrhage, massive hepatic necrosis, enhanced oxidative stress, elevated hypoxia, and extensive infiltration of CD11b\n                    <jats:sup>+<\/jats:sup>\n                    inflammatory cells into hepatic microenvironments rich for connective tissue growth factor (Ctgf) during ethanol\/CCl\n                    <jats:sub>4<\/jats:sub>\n                    \u2010induced liver damage. Analysis of whole\u2010genome transcriptomics indicated upregulation of genes involved in hypoxia and extracellular matrix (ECM) remodeling, whereas genes related to hepatocyte proliferation, progenitor cell activation, and ethanol detoxification were downregulated in the damaged livers of\n                    <jats:italic>Yap1<\/jats:italic>\n                    \u00a0KO.\n                    <jats:italic>Acetaldehyde dehydrogenase (Aldh)1a1<\/jats:italic>\n                    ,\n                    <jats:italic>a<\/jats:italic>\n                    gene that encodes a detoxification enzyme for aldehyde substrates, was identified as a potential YAP target because this gene could be transcriptionally activated by a hyperactive YAP mutant. The ectopic expression of the human\n                    <jats:italic>ALDH1A1<\/jats:italic>\n                    \u00a0gene caused increase in hepatocyte proliferation and decrease in hepatic necrosis, oxidative stress, ECM remodeling, and inflammation during ethanol\/CCl\n                    <jats:sub>4<\/jats:sub>\n                    \u2010induced liver damage. Taken together, these observations indicated that YAP was crucial for liver repair during alcohol\u2010associated injury. Its regulation of ALDH1A1 represents a new link in liver regeneration and detoxification.\n                  <\/jats:p>","DOI":"10.1096\/fj.202101686r","type":"journal-article","created":{"date-parts":[[2022,2,26]],"date-time":"2022-02-26T14:14:49Z","timestamp":1645884889000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Liver regeneration and ethanol detoxification: A new link in YAP regulation of ALDH1A1 during alcohol\u2010related hepatocyte damage"],"prefix":"10.1096","volume":"36","author":[{"given":"Junmei","family":"Zhou","sequence":"first","affiliation":[{"name":"Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair The Affiliated Hospital of Guilin Medical University  Guilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunbao","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pathology Tulane University  New Orleans Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Systems Biology Beckman Research Institute of the City of Hope  Duarte California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhui","family":"Wang","sequence":"additional","affiliation":[{"name":"Integrative Genomics Core Beckman Research Institute of the City of Hope  Duarte California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natacha","family":"Jn\u2010Simon","sequence":"additional","affiliation":[{"name":"Department of Pathology Tulane University  New Orleans Louisiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry University of Florida  Gainesville Florida 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