{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:23:48Z","timestamp":1787027028885,"version":"build-2736575974"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    <jats:bold>Background:<\/jats:bold>\n                    Alcoholic liver disease (ALD) caused by chronic ethanol overconsumption is a common type of liver disease with a severe mortality burden throughout the world. The pathogenesis of ALD is complex, and no effective clinical treatment for the disease has advanced so far. Prolonged alcohol abstinence is the most effective therapy to attenuate the clinical course of ALD and even reverse liver damage. However, the molecular mechanisms involved in alcohol abstinence-improved recovery from alcoholic fatty liver remain unclear. This study aims to systematically evaluate the beneficial effect of alcohol abstinence on pathological changes in ALD.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    Using the Lieber-DeCarli mouse model of ALD, we analysed whether 1-week alcohol withdrawal reversed alcohol-induced detrimental alterations, including oxidative stress, liver injury, lipids metabolism, and hepatic inflammation, by detecting biomarkers and potential targets.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    Alcohol withdrawal ameliorated alcohol-induced hepatic steatosis by improving liver lipid metabolism reprogramming\n                    <jats:italic>via<\/jats:italic>\n                    upregulating phosphorylated 5\u2032-AMP -activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor-\u03b1 (PPAR-\u03b1), and carnitine palmitoyltransferase-1 (CPT-1), and downregulating fatty acid synthase (FAS) and diacylglycerol acyltransferase-2 (DGAT-2). The activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), were significantly enhanced by alcohol withdrawal. Importantly, the abstinence recovered alcohol-fed induced liver injury, as evidenced by the improvements in haematoxylin and eosin (H&amp;amp;E) staining, plasma alanine aminotransferase (ALT) levels, and liver weight\/body weight ratio. Alcohol-stimulated toll-like receptor 4\/mitogen-activated protein kinases (TLR4\/MAPKs) were significantly reversed by alcohol withdrawal, which might mechanistically contribute to the amelioration of liver injury. Accordingly, the hepatic inflammatory factor represented by tumour necrosis factor-alpha (TNF-\u03b1) was improved by alcohol abstinence.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusion:<\/jats:bold>\n                    In summary, we reported that alcohol withdrawal effectively restored hepatic lipid metabolism and reversed liver injury and inflammation by improving metabolism reprogramming. These findings enhanced our understanding of the biological mechanisms involved in the beneficial role of alcohol abstinence as an effective treatment for ALD.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2021.752148","type":"journal-article","created":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T01:03:37Z","timestamp":1631754217000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":26,"title":["Alcohol Abstinence Rescues Hepatic Steatosis and Liver Injury via Improving Metabolic Reprogramming in Chronic Alcohol-Fed Mice"],"prefix":"10.3389","volume":"12","author":[{"given":"Aiwen","family":"Pi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinchao","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanglei","family":"Lai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibin","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linfeng","family":"Chi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songtao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1016\/j.jhep.2016.04.029","article-title":"Treatment of Alcohol Use Disorders in Patients with Alcoholic Liver Disease","volume":"65","author":"Addolorato","year":"2016","journal-title":"J. Hepatol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1159\/000324280","article-title":"Animal Models of Alcoholic Liver Disease","volume":"28","author":"Arteel","year":"2010","journal-title":"Dig. Dis."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1002\/hep.510230513","article-title":"Prediction of Risk of Liver Disease by Alcohol Intake, Sex, and Age: a Prospective Population Study","volume":"23","author":"Becker","year":"1996","journal-title":"Hepatology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1111\/j.1530-0277.1989.tb00323.x","article-title":"Ethanol-induced Impairments in Receptor-Mediated Endocytosis of Asialoorosomucoid in Isolated Rat Hepatocytes: Time Course of Impairments and Recovery after Ethanol Withdrawal","volume":"13","author":"Casey","year":"1989","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"17756","DOI":"10.3748\/wjg.v20.i47.17756","article-title":"Pathogenesis of Alcoholic Liver Disease: Role of Oxidative Metabolism","volume":"20","author":"Ceni","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1111\/acer.14265","article-title":"RNA Sequencing Reveals a Comprehensive Circular RNA Expression Profile in a Mouse Model of Alcoholic Liver Disease","volume":"44","author":"Dou","year":"2020","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s12276-017-0013-x","article-title":"Glutathione Disulfide Sensitizes Hepatocytes to TNF\u03b1-Mediated Cytotoxicity via IKK-\u03b2 S-Glutathionylation: a Potential Mechanism Underlying Non-alcoholic Fatty Liver Disease","volume":"50","author":"Dou","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"27997","DOI":"10.1074\/jbc.M302140200","article-title":"Peroxisome Proliferator-Activated Receptor Alpha (PPARalpha) Agonist Treatment Reverses PPARalpha Dysfunction and Abnormalities in Hepatic Lipid Metabolism in Ethanol-Fed Mice","volume":"278","author":"Fischer","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1016\/j.cell.2020.02.041","article-title":"Toll-like Receptors and the Control of Immunity","volume":"180","author":"Fitzgerald","year":"2020","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/s41395-018-0076-x","article-title":"ACG Clinical Guideline for Alcoholic Liver Disease: The MELD Threshold for Corticosteroid Treatment Has yet to Be Established","volume":"114","author":"Forrest","year":"2019","journal-title":"Am. J. Gastroenterol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD Development and Therapeutic Strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1074\/jbc.M008791200","article-title":"The Transcriptional and DNA Binding Activity of Peroxisome Proliferator-Activated Receptor Alpha Is Inhibited by Ethanol Metabolism. A Novel Mechanism for the Development of Ethanol-Induced Fatty Liver","volume":"276","author":"Galli","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1053\/j.gastro.2016.01.025","article-title":"Inflammation in Alcoholic and Nonalcoholic Fatty Liver Disease: Friend or Foe?","volume":"150","author":"Gao","year":"2016","journal-title":"Gastroenterology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1111\/j.1440-1681.2009.05152.x","article-title":"Overexpression of Aldehyde Dehydrogenase-2 Attenuates Chronic Alcohol Exposure-Induced Apoptosis, Change in Akt and Pim Signalling in Liver","volume":"36","author":"Guo","year":"2009","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1002\/Hep.21138","article-title":"Differential Liver Sensitization to Toll-like Receptor Pathways in Mice with Alcoholic Fatty Liver","volume":"43","author":"Gustot","year":"2006","journal-title":"Hepatology"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1002\/Hep.22470","article-title":"The Critical Role of Toll-like Receptor (Tlr) 4 in Alcoholic Liver Disease Is Independent of the Common Tlr Adapter Myd88","volume":"48","author":"Hritz","year":"2008","journal-title":"Hepatology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1002\/Hep.24708","article-title":"Regulation of Hepatic Lipin-1 by Ethanol: Role of Amp-Activated Protein Kinase\/Sterol Regulatory Element-Binding Protein 1 Signaling in Mice","volume":"55","author":"Hu","year":"2012","journal-title":"Hepatology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1016\/S0016-5085(03)00276-2","article-title":"Betaine Decreases Hyperhomocysteinemia, Endoplasmic Reticulum Stress, and Liver Injury in Alcohol-Fed Mice","volume":"124","author":"Ji","year":"2003","journal-title":"Gastroenterology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.amjmed.2016.10.004","article-title":"Treatment of Alcohol Use Disorder in Patients with Alcoholic Liver Disease","volume":"130","author":"Leggio","year":"2017","journal-title":"Am. J. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.jhep.2012.08.018","article-title":"CYP2E1 and Oxidant Stress in Alcoholic and Non-alcoholic Fatty Liver Disease","volume":"58","author":"Leung","year":"2013","journal-title":"J. Hepatol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"560905","DOI":"10.3389\/fphar.2020.560905","article-title":"Activation of the AMPK-SIRT1 Pathway Contributes to Protective Effects of Salvianolic Acid A against Lipotoxicity in Hepatocytes and NAFLD in Mice","volume":"11","author":"Li","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.redox.2014.08.009","article-title":"The Role of Reactive Oxygen Species (ROS) and Cytochrome P-450 2E1 in the Generation of Carcinogenic Etheno-DNA Adducts","volume":"3","author":"Linhart","year":"2014","journal-title":"Redox Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.2174\/1381612824666180410091511","article-title":"Cytochrome P450s and Alcoholic Liver Disease","volume":"24","author":"Lu","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.3389\/fphys.2019.01042","article-title":"Hepatic SIRT3 Upregulation in Response to Chronic Alcohol Consumption Contributes to Alcoholic Liver Disease in Mice","volume":"10","author":"Ma","year":"2019","journal-title":"Front. Physiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1111\/acer.13546","article-title":"Carcinogenic Etheno DNA Adducts in Alcoholic Liver Disease: Correlation with Cytochrome P-4502E1 and Fibrosis","volume":"42","author":"Mueller","year":"2018","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21010265","article-title":"Cryptotanshinone from the Salvia Miltiorrhiza Bunge Attenuates Ethanol-Induced Liver Injury by Activation of AMPK\/SIRT1 and Nrf2 Signaling Pathways","volume":"21","author":"Nagappan","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"972","DOI":"10.1002\/hep.20399","article-title":"Peroxisome Proliferator-Activated Receptor Alpha Protects against Alcohol-Induced Liver Damage","volume":"40","author":"Nakajima","year":"2004","journal-title":"Hepatology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1124\/jpet.103.064717","article-title":"Alcoholic Liver Injury in the Rat Is Associated with Reduced Expression of Peroxisome Proliferator-Alpha (PPARalpha)-Regulated Genes and Is Ameliorated by PPARalpha Activation","volume":"310","author":"Nanji","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B29","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1002\/hep.23258","article-title":"Alcoholic Liver Disease","volume":"51","author":"O'shea","year":"2010","journal-title":"Hepatology"},{"key":"B30","first-page":"147","article-title":"Alcoholic Liver Disease: Pathogenesis and Current Management","volume":"38","author":"Osna","year":"2017","journal-title":"Alcohol. Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1111\/j.1530-0277.2008.00827.x","article-title":"Molecular Mechanisms of Alcoholic Fatty Liver","volume":"33","author":"Purohit","year":"2009","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"201S","DOI":"10.1038\/oby.2006.309","article-title":"Fatty Acid Metabolism, the central Nervous System, and Feeding","volume":"14","author":"Ronnett","year":"2006","journal-title":"Obesity (Silver Spring)"},{"key":"B33","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41572-018-0014-7","article-title":"Alcoholic Liver Disease","volume":"4","author":"Seitz","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B34","doi-asserted-by":"publisher","first-page":"3572","DOI":"10.1111\/jcmm.13636","article-title":"The TLR4-Ire1\u03b1 Pathway Activation Contributes to Palmitate-Elicited Lipotoxicity in Hepatocytes","volume":"22","author":"Shen","year":"2018","journal-title":"J. Cel Mol Med"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.alcohol.2020.10.002","article-title":"Dihydromyricetin Improves Mitochondrial Outcomes in the Liver of Alcohol-Fed Mice via the AMPK\/Sirt-1\/PGC-1\u03b1 Signaling axis","volume":"91","author":"Silva","year":"2021","journal-title":"Alcohol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/ajg.2017.469","article-title":"ACG Clinical Guideline: Alcoholic Liver Disease","volume":"113","author":"Singal","year":"2018","journal-title":"Am. J. Gastroenterol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"G509","DOI":"10.1152\/ajpgi.00376.2018","article-title":"Ethanol Withdrawal Mitigates Fatty Liver by Normalizing Lipid Catabolism","volume":"316","author":"Thomes","year":"2019","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1053\/jhep.2001.25350","article-title":"Toll-like Receptor 4 Is Involved in the Mechanism of Early Alcohol-Induced Liver Injury in Mice","volume":"34","author":"Uesugi","year":"2001","journal-title":"Hepatology"},{"key":"B39","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1152\/ajpendo.1999.277.1.E1","article-title":"AMP-activated Protein Kinase, a Metabolic Master Switch: Possible Roles in Type 2 Diabetes","volume":"277","author":"Winder","year":"1999","journal-title":"Am. J. Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.pharmthera.2017.06.007","article-title":"Targeting Inflammation for the Treatment of Alcoholic Liver Disease","volume":"180","author":"Xu","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"B41","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1111\/j.1530-0277.1995.tb00958.x","article-title":"Apoptosis and Bcl-2 Protein Expression in Experimental Alcoholic Liver Disease in the Rat","volume":"19","author":"Yacoub","year":"1995","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"B42","doi-asserted-by":"publisher","first-page":"627123","DOI":"10.3389\/fphar.2021.627123","article-title":"Inhibition of TLR4\/MAPKs Pathway Contributes to the Protection of Salvianolic Acid A against Lipotoxicity-Induced Myocardial Damage in Cardiomyocytes and Obese Mice","volume":"12","author":"Yang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"29342","DOI":"10.1074\/jbc.M202411200","article-title":"Ethanol Induces Fatty Acid Synthesis Pathways by Activation of Sterol Regulatory Element-Binding Protein (SREBP)","volume":"277","author":"You","year":"2002","journal-title":"J. Biol. Chem."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1798","DOI":"10.1053\/j.gastro.2004.09.049","article-title":"The Role of AMP-Activated Protein Kinase in the Action of Ethanol in the Liver","volume":"127","author":"You","year":"2004","journal-title":"Gastroenterology"},{"key":"B45","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global Epidemiology of Nonalcoholic Fatty Liver Disease-Meta-Analytic Assessment of Prevalence, Incidence, and Outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"B46","doi-asserted-by":"publisher","first-page":"2032","DOI":"10.1002\/hep.22010","article-title":"Determinants of Alcohol Use and Abuse: Impact of Quantity and Frequency Patterns on Liver Disease","volume":"46","author":"Zakhari","year":"2007","journal-title":"Hepatology"},{"key":"B47","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/s0168-8278(00)00047-7","article-title":"Clinical and Biological Relevance of Hepatocyte Apoptosis in Alcoholic Hepatitis","volume":"34","author":"Ziol","year":"2001","journal-title":"J. Hepatol."}],"updated-by":[{"DOI":"10.3389\/fphar.2025.1554390","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T00:00:00Z","timestamp":1739923200000}}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.752148\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T03:17:56Z","timestamp":1739935076000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2021.752148\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,16]]},"references-count":47,"alternative-id":["10.3389\/fphar.2021.752148"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2021.752148","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,16]]},"article-number":"752148"}}