{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T05:27:58Z","timestamp":1770960478347,"version":"3.50.1"},"reference-count":43,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2015,11,20]],"date-time":"2015-11-20T00:00:00Z","timestamp":1447977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57\/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration,  3.5 g\/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9\/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute\/binge ethanol induced acceleration of alcoholic liver disease.<\/jats:p>","DOI":"10.3390\/biom5043280","type":"journal-article","created":{"date-parts":[[2015,11,24]],"date-time":"2015-11-24T01:57:02Z","timestamp":1448330222000},"page":"3280-3294","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses"],"prefix":"10.3390","volume":"5","author":[{"given":"Shivendra","family":"Shukla","sequence":"first","affiliation":[{"name":"Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MI 65212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9203-4280","authenticated-orcid":false,"given":"Annayya","family":"Aroor","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MI 65212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricardo","family":"Restrepo","sequence":"additional","affiliation":[{"name":"Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri, Columbia, MI 65212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kusum","family":"Kharbanda","sequence":"additional","affiliation":[{"name":"Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamal","family":"Ibdah","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, University of Missouri, Columbia, MI 65212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2015,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1111\/acer.12011","article-title":"Binge ethanol and liver: New molecular developments","volume":"37","author":"Shukla","year":"2013","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_2","doi-asserted-by":"crossref","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":"ref_3","doi-asserted-by":"crossref","first-page":"2223","DOI":"10.1016\/S0140-6736(09)60746-7","article-title":"Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders","volume":"373","author":"Rehm","year":"2009","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1136\/gut.2007.145573","article-title":"Effect of binge drinking on the liver: An alarming public health issue?","volume":"58","author":"Mathurin","year":"2009","journal-title":"Gut"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1097\/CHI.0b013e3181a2b32f","article-title":"Binge drinking among youths and young adults in the United States: 1979\u20132006","volume":"48","author":"Grucza","year":"2009","journal-title":"J. Am. Acad. Child Adolesc. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1037\/a0014414","article-title":"Binge drinking in young adults: Data, definitions, and determinants","volume":"135","author":"Courtney","year":"2009","journal-title":"Psychol. Bull."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1097\/01.mcg.0000225570.04773.5d","article-title":"Acute alcoholic hepatitis","volume":"40","author":"Ceccanti","year":"2006","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1111\/j.1365-2036.2007.03302.x","article-title":"Fibrosis progression occurs in a subgroup of heavy drinkers with typical histological features","volume":"25","author":"Mathurin","year":"2007","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s11938-002-0029-7","article-title":"Alcoholic hepatitis","volume":"5","author":"Crosse","year":"2002","journal-title":"Curr. Treat Options Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1111\/j.1751-2980.2011.00569.x","article-title":"Oxidative stress and redox signaling mechanisms of alcoholic liver disease: Updated experimental and clinical evidence","volume":"13","author":"Zhu","year":"2012","journal-title":"J. Dig. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1097\/MCO.0b013e32835a892a","article-title":"Methionine metabolic pathway in alcoholic liver injury","volume":"16","author":"Kharbanda","year":"2013","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1172\/JCI37409","article-title":"Adenosine signaling contributes to ethanol-induced fatty liver in mice","volume":"119","author":"Peng","year":"2009","journal-title":"J. Clin. Invest."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.1096\/fj.07-100685","article-title":"Ecto-5'-nucleotidase (CD73)-mediated extracellular adenosine production plays a critical role in hepatic fibrosis","volume":"22","author":"Peng","year":"2008","journal-title":"FASEB J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5265","DOI":"10.3748\/wjg.v12.i33.5265","article-title":"Epigenetic effects of ethanol on liver and gastrointestinal injury","volume":"12","author":"Shukla","year":"2006","journal-title":"World J. Gastroenterol."},{"key":"ref_15","first-page":"47","article-title":"Epigenetic effects of ethanol on the liver and gastrointestinal system","volume":"35","author":"Shukla","year":"2013","journal-title":"Alcohol Res. Curr. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1146\/annurev-biochem-072711-165700","article-title":"Readout of epigenetic modifications","volume":"82","author":"Patel","year":"2013","journal-title":"Annu. Rev. Biochem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.gde.2012.11.006","article-title":"Chromatin organization and transcriptional regulation","volume":"23","author":"Spector","year":"2013","journal-title":"Curr. Opin. Genet Dev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.lfs.2007.07.030","article-title":"Distinct methylation patterns in histone H3 at Lys-4 and Lys-9 correlate with up- and down-regulation of genes by ethanol in hepatocytes","volume":"81","author":"Bhadra","year":"2007","journal-title":"Life Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1124\/jpet.115.223867","article-title":"Different mechanisms for histone acetylation by ethanol and its metabolite acetate in rat primary hepatocytes","volume":"354","author":"Shukla","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1093\/alcalc\/agh248","article-title":"Acute in vivo effect of ethanol (binge drinking) on histone H3 modifications in rat tissues","volume":"41","author":"Kim","year":"2006","journal-title":"Alcohol Alcohol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1920","DOI":"10.1111\/acer.12172","article-title":"Binge ethanol-induced HDAC3 down-regulates Cpt1\u03b1 expression leading to hepatic steatosis and injury","volume":"37","author":"Kirpich","year":"2013","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1124\/jpet.111.186775","article-title":"Histone H3 phosphorylation (Ser10, Ser28) and phosphoacetylation (K9S10) are differentially associated with gene expression in liver of rats treated in vivo with acute ethanol","volume":"340","author":"James","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1111\/j.1530-0277.2010.01239.x","article-title":"Differential changes in MAP kinases, histone modifications, and liver injury in rats acutely treated with ethanol","volume":"34","author":"Aroor","year":"2010","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s12263-009-0158-x","article-title":"Gene expression modifications in the liver caused by binge drinking and S-adenosylmethionine feeding. The role of epigenetic changes","volume":"5","author":"Li","year":"2010","journal-title":"Genes Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1002\/hep.23382","article-title":"Epigenetic regulation of hepatic endoplasmic reticulum stress pathways in the ethanol-fed cystathionine beta synthase-deficient mouse","volume":"51","author":"Esfandiari","year":"2010","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1093\/alcalc\/ags004","article-title":"Gene-selective histone H3 acetylation in the absence of increase in global histone acetylation in liver of rats chronically fed alcohol","volume":"47","author":"Park","year":"2012","journal-title":"Alcohol Alcohol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1111\/j.1530-0277.2008.00729.x","article-title":"Emerging role of epigenetics in the actions of alcohol","volume":"32","author":"Shukla","year":"2008","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1093\/jn\/138.3.497","article-title":"Mammalian sirtuin 1 is involved in the protective action of dietary saturated fat against alcoholic fatty liver in mice","volume":"138","author":"You","year":"2008","journal-title":"J. Nutr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1111\/j.1530-0277.2011.01577.x","article-title":"Elevated activation of ERK1 and ERK2 accompany enhanced liver injury following alcohol binge in chronically ethanol-fed rats","volume":"35","author":"Aroor","year":"2011","journal-title":"Alcohol Clin. Exp. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s12072-014-9546-4","article-title":"Epigenetic histone modifications in a clinically relevant rat model of chronic ethanol-binge-mediated liver injury","volume":"8","author":"Aroor","year":"2014","journal-title":"Hepatol. Int."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1002\/hep.23391","article-title":"Differences in betaine-homocysteine methyl transferase expression, endoplasmic reticulum stress response, and liver injury between alcohol-fed mice and rats","volume":"51","author":"Shinohara","year":"2010","journal-title":"Hepatology"},{"key":"ref_32","doi-asserted-by":"crossref","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":"ref_33","doi-asserted-by":"crossref","unstructured":"Aroor, A.R., Roy, L.J., Restrepo, R.J., Mooney, B.P., and Shukla, S.D. (2012). A proteomic analysis of liver after ethanol binge in chronically ethanol treated rats. Proteome Sci.","DOI":"10.1186\/1477-5956-10-29"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1038\/emboj.2010.27","article-title":"A cooperative activation loop among SWI\/SNF, gamma-H2AX and H3 acetylation for DNA double-strand break repair","volume":"29","author":"Lee","year":"2010","journal-title":"EMBO J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"31954","DOI":"10.1074\/jbc.M110.148718","article-title":"Activator-dependent p300 acetylation of chromatin in vitro: Enhancement of transcription by disruption of repressive nucleosome-nucleosome interactions","volume":"285","author":"Szerlong","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.alcohol.2010.12.003","article-title":"Knock down of GCN5 histone acetyltransferase by siRNA decreases ethanol-induced histone acetylation and affects differential expression of genes in human hepatoma cells","volume":"45","author":"Choudhury","year":"2011","journal-title":"Alcohol"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1074\/jbc.274.3.1189","article-title":"Overlapping but distinct patterns of histone acetylation by the human coactivators p300 and PCAF within nucleosomal substrates","volume":"274","author":"Schiltz","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ejphar.2011.12.045","article-title":"Dysregulated phosphorylation and nuclear translocation of cyclic AMP response element binding protein (CREB) in rat liver after chronic ethanol binge","volume":"679","author":"Aroor","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1002\/hep.510310219","article-title":"The glutathione precursor l-2-oxothiazolidine-4-carboxylic acid protects against liver injury due to chronic enteral ethanol exposure in the rat","volume":"31","author":"Iimuro","year":"2000","journal-title":"Hepatology"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Kharbanda, K.K., Todero, S.L., King, A.L., Osna, N.A., McVicker, B.L., Tuma, D.J., Wisecarver, J.L., and Bailey, S.M. (2012). Betaine treatment attenuates chronic ethanol-induced hepatic steatosis and alterations to the mitochondrial respiratory chain proteome. Int. J. Hepatol.","DOI":"10.1155\/2012\/962183"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"32198","DOI":"10.1074\/jbc.M803446200","article-title":"G9a and HP1 couple histone and DNA methylation to TNF\u03b1 transcription silencing during endotoxin tolerance","volume":"283","author":"Yoza","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1161\/ATVBAHA.109.193821","article-title":"Phosphorylation and acetylation of histone H3 and autoregulation by early growth response 1 mediate interleukin 1\u03b2 induction of early growth response 1 transcription","volume":"30","author":"Wang","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.alcohol.2012.08.004","article-title":"Rodent models of alcoholic liver disease: Of mice and men","volume":"46","author":"Schrum","year":"2012","journal-title":"Alcohol"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/5\/4\/3280\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:52:32Z","timestamp":1760215952000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/5\/4\/3280"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,20]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2015,12]]}},"alternative-id":["biom5043280"],"URL":"https:\/\/doi.org\/10.3390\/biom5043280","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,11,20]]}}}