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Increased hepatocyte apoptosis is critical for progression of liver inflammation, stellate cell activation, and fibrosis. Using hepatocyte\u2010specific <jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>1<jats:italic>\u03b1<\/jats:italic>\u2010deficient mice (\u0394HepHIF1<jats:italic>\u03b1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>), here we investigated the contribution of <jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>1<jats:italic>\u03b1<\/jats:italic> to ethanol\u2010induced hepatocyte apoptosis and its role in amplification of fibrosis after carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) exposure. Moderate ethanol feeding (11% of kcal) induced accumulation of hypoxia\u2010sensitive pimonidazole adducts and <jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>1<jats:italic>\u03b1<\/jats:italic> expression in the liver within 4\u00a0days of ethanol feeding. Chronic CCl<jats:sub>4<\/jats:sub> treatment increased M30\u2010positive cells, a marker of hepatocyte apoptosis in pair\u2010fed control mice. Concomitant ethanol feeding (11% of kcal) amplified CCl<jats:sub>4<\/jats:sub>\u2010induced hepatocyte apoptosis in livers of wild\u2010type mice, associated with elevated p53<jats:sup>K386<\/jats:sup> acetylation, <jats:styled-content style=\"fixed-case\">PUMA<\/jats:styled-content> expression, and Ly6c<jats:sup>+<\/jats:sup> cell infiltration. Subsequent to increased apoptosis, ethanol\u2010enhanced induction of profibrotic markers, including stellate cell activation, collagen 1 expression, and extracellular matrix deposition following CCl<jats:sub>4<\/jats:sub> exposure. Ethanol\u2010induced exacerbation of hepatocyte apoptosis, p53<jats:sup>K386<\/jats:sup> acetylation, and <jats:styled-content style=\"fixed-case\">PUMA<\/jats:styled-content> expression following CCl<jats:sub>4<\/jats:sub> exposure was attenuated in livers of \u0394Hep<jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>1<jats:italic>\u03b1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. This protection was also associated with a reduction in Ly6c<jats:sup>+<\/jats:sup> cell infiltration and decreased fibrosis in livers of \u0394Hep<jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>1<jats:italic>\u03b1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice. In summary, these results indicate that moderate ethanol exposure leads to hypoxia\/<jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>1<jats:italic>\u03b1<\/jats:italic>\u2010mediated signaling in hepatocytes and induction of p53\u2010dependent apoptosis of hepatocytes, resulting in increased hepatic fibrosis during chronic CCl<jats:sub>4<\/jats:sub> exposure.<\/jats:p>","DOI":"10.1002\/prp2.61","type":"journal-article","created":{"date-parts":[[2014,7,24]],"date-time":"2014-07-24T09:36:29Z","timestamp":1406194589000},"source":"Crossref","is-referenced-by-count":25,"title":["Moderate, chronic ethanol feeding exacerbates carbon tetrachloride\u2013induced hepatic fibrosis via hepatocyte\u2010specific hypoxia\u2010inducible factor 1<i>\u03b1<\/i>"],"prefix":"10.1002","volume":"2","author":[{"given":"Sanjoy","family":"Roychowdhury","sequence":"first","affiliation":[{"name":"Center for Liver Disease Research Department of Pathobiology Lerner Research Institute, Cleveland 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