{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T18:08:57Z","timestamp":1787076537920,"version":"build-2736575974"},"reference-count":53,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,4,17]],"date-time":"2022-04-17T00:00:00Z","timestamp":1650153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA029241\u201001"],"award-info":[{"award-number":["AA029241\u201001"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alcoholism Clin &amp;amp; Exp Res"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Hepatic steatosis is an early pathology of alcohol\u2010associated liver disease (ALD). Fatty acid\u2010binding protein\u20104 (FABP4, a FABP not normally produced in the liver) is secreted by hepatocytes in ALD and stimulates hepatoma proliferation and migration. This study sought to investigate the mechanism[s] by which hepatic ethanol metabolism regulates FABP4 and steatosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human hepatoma cells (HepG2\/HuH7) and cells stably transfected to express cytochrome P450 2E1 (CYP2E1), were exposed to ethanol in the absence or presence of chlormethiazole (a CYP2E1\u2010inhibitor; CMZ) and\/or EX\u2010527 (a sirtuin\u20101 [SIRT1] inhibitor). The culture medium was analyzed for ethanol metabolism and FABP4 protein abundance. Cells were analyzed for <jats:italic>FABP4<\/jats:italic>\u00a0mRNA expression, SIRT1 protein abundance, and neutral lipid accumulation. In parallel, cells were analyzed for forkhead box O1 [FOXO1], \u03b2\u2010catenin, peroxisome proliferator\u2010activated receptor\u2010\u03b1 [PPAR\u03b1], and lipin\u20101\u03b1 protein abundance in the absence or presence of ethanol and pharmacological inhibitors of the respective target proteins.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CYP2E1\u2010dependent ethanol metabolism inhibited the amount of SIRT1 protein detected, concomitant with increased <jats:italic>FABP4<\/jats:italic>\u00a0mRNA expression, FABP4 protein secretion, and neutral lipid accumulation, effects abolished by CMZ. Analysis of pathways associated with lipid oxidation revealed increased FOXO1 nuclear localization and decreased \u03b2\u2010catenin, PPAR\u03b1, and lipin\u20101\u03b1 protein levels in CYP2E1\u2010expressing cells in the presence of ethanol. Pharmacological inhibition of SIRT1\u00a0mimicked the effects of ethanol, while inhibition of FOXO1 abrogated the effect of ethanol on <jats:italic>FABP4<\/jats:italic>\u00a0mRNA expression, FABP4 protein secretion, and neutral lipid accumulation in CYP2E1\u2010expressing cells. Pharmacological inhibition of \u03b2\u2010catenin, PPAR\u03b1, or lipin\u20101\u03b1 failed to alter the effects of ethanol on FABP4 or neutral lipid accumulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>CYP2E1\u2010dependent ethanol metabolism inhibits SIRT1\u2010FOXO1\u00a0signaling, which leads to increased <jats:italic>FABP4<\/jats:italic>\u00a0mRNA expression, FABP4 protein secretion, and neutral lipid accumulation. These data suggest that FABP4 released from steatotic hepatocytes could play a role in promoting tumor cell expansion in the setting of ALD and represents a potential target for therapeutic intervention.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.14828","type":"journal-article","created":{"date-parts":[[2022,4,11]],"date-time":"2022-04-11T06:43:15Z","timestamp":1649659395000},"page":"928-940","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Cytochrome P450 2E1\u2010dependent hepatic ethanol metabolism induces fatty acid\u2010binding protein 4 and steatosis"],"prefix":"10.1111","volume":"46","author":[{"given":"Neha","family":"Attal","sequence":"first","affiliation":[{"name":"Department of Surgery Carolinas Medical Center Atrium Health  Charlotte North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Marrero","sequence":"additional","affiliation":[{"name":"Department 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