{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:40:08Z","timestamp":1790628008837,"version":"4.1.0"},"reference-count":45,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T00:00:00Z","timestamp":1667520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institutes of Health\u2014National Institute of Alcohol Abuse &amp; Alcoholism","doi-asserted-by":"publisher","award":["AA029241"],"award-info":[{"award-number":["AA029241"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Fatty acid binding protein-4 (FABP4) is not normally expressed in the liver but is induced in alcohol-dependent liver disease (ALD)). This study sought to identify mechanisms whereby ethanol (EtOH) metabolism alters triglyceride accumulation and FABP4 production. Human hepatoma cells which were stably transfected to express alcohol dehydrogenase (ADH) or cytochrome P4502E1 (CYP2E1) were exposed to EtOH in the absence\/presence of inhibitors of ADH (4-methylpyrazole) or CYP2E1 (chlormethiazole). Cells were analyzed for free fatty acid (FFA) content and FABP4 mRNA, then culture medium assayed for FABP4 levels. Cell lysates were analyzed for AMP-activated protein kinase-\u03b1 (AMPK\u03b1), Acetyl-CoA carboxylase (ACC), sterol regulatory element binding protein-1c (SREBP-1c), and Lipin-1\u03b2 activity and localization in the absence\/presence of EtOH and pharmacological inhibitors. CYP2E1-EtOH metabolism led to increased FABP4 mRNA\/protein expression and FFA accumulation. Analysis of signaling pathway activity revealed decreased AMPK\u03b1 activation and increased nuclear-SREBP-1c localization following CYP2E1-EtOH metabolism. The role of AMPK\u03b1-SREBP-1c in regulating CYP2E1-EtOH-dependent FFA accumulation and increased FABP4 was confirmed using pharmacological inhibitors and over-expression of AMPK\u03b1. Inhibition of ACC or Lipin-1\u03b2 failed to prevent FFA accumulation or changes in FABP4 mRNA expression or protein secretion. These data suggest that CYP2E1-EtOH metabolism inhibits AMPK\u03b1 phosphorylation to stimulate FFA accumulation and FABP4 protein secretion via an SREBP-1c dependent mechanism.<\/jats:p>","DOI":"10.3390\/biology11111613","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T04:00:51Z","timestamp":1667534451000},"page":"1613","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Role of AMPK-SREBP Signaling in Regulating Fatty Acid Binding-4 (FABP4) Expression following Ethanol Metabolism"],"prefix":"10.3390","volume":"11","author":[{"given":"Neha","family":"Attal","sequence":"first","affiliation":[{"name":"Department of Surgery, Atrium Health-Carolinas Medical Center, 1000 Blythe Blvd., Charlotte, NC 28203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Marrero","sequence":"additional","affiliation":[{"name":"Department of Surgery, Atrium Health-Carolinas Medical Center, 1000 Blythe Blvd., Charlotte, NC 28203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle J.","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Surgery, Atrium Health-Carolinas Medical Center, 1000 Blythe Blvd., Charlotte, NC 28203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2666-6727","authenticated-orcid":false,"given":"Iain H.","family":"McKillop","sequence":"additional","affiliation":[{"name":"Department of Surgery, Atrium Health-Carolinas Medical Center, 1000 Blythe Blvd., Charlotte, NC 28203, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"29","DOI":"10.2217\/hep.15.40","article-title":"Role of alcohol in the development and progression of hepatocellular carcinoma","volume":"3","author":"McKillop","year":"2016","journal-title":"Hepatic Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.toxrep.2021.02.010","article-title":"Alcohol-associated liver disease: A review on its pathophysiology, diagnosis and drug therapy","volume":"8","author":"Subramaniyan","year":"2021","journal-title":"Toxicol. 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