{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T13:03:18Z","timestamp":1768482198197,"version":"3.49.0"},"reference-count":35,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T00:00:00Z","timestamp":1690502400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS)","award":["JP25460879"],"award-info":[{"award-number":["JP25460879"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["16K09223"],"award-info":[{"award-number":["16K09223"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Lipid accumulation in the liver due to chronic alcohol consumption (CAC) is crucial in the development of alcohol liver disease (ALD). It is promoted by the NADH\/NAD ratio increase via alcohol dehydrogenase (ADH)-dependent alcohol metabolism and lipogenesis increase via peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3) in the liver. The transcriptional activity of PPAR\u03b3 on lipogenic genes is inhibited by S-nitrosylation but activated by denitrosylation via S-nitrosoglutathione reductase (GSNOR), an enzyme identical to ADH3. Besides ADH1, ADH3 also participates in alcohol metabolism. Therefore, we investigated the specific contribution of ADH3 to ALD onset. ADH3-knockout (Adh3-\/-) and wild-type (WT) mice were administered a 10% ethanol solution for 12 months. Adh3-\/- exhibited no significant pathological changes in the liver, whereas WT exhibited marked hepatic lipid accumulation (p &lt; 0.005) with increased serum transaminase levels. Adh3-\/- exhibited no death during CAC, whereas WT exhibited a 40% death. Liver ADH3 mRNA levels were elevated by CAC in WT (p &lt; 0.01). The alcohol elimination rate measured after injecting 4 g\/kg ethanol was not significantly different between two strains, although the rate was increased in both strains by CAC. Thus, ADH3 plays a key role in the ALD onset, likely by acting as GSNOR.<\/jats:p>","DOI":"10.3390\/ijms241512102","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T07:35:24Z","timestamp":1690529724000},"page":"12102","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Class III Alcohol Dehydrogenase Plays a Key Role in the Onset of Alcohol-Related\/-Associated Liver Disease as an S-Nitrosoglutathione Reductase in Mice"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1060-927X","authenticated-orcid":false,"given":"Takeshi","family":"Haseba","sequence":"first","affiliation":[{"name":"Department of Legal Medicine, Kanagawa Dental University, 82 Inaokacho, Yokosuka 238-8580, Japan"},{"name":"Department of Legal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motoyo","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Division of Laboratory Animal Science, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshio","family":"Akimoto","sequence":"additional","affiliation":[{"name":"Division of Laboratory Animal Science, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isao","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Legal Medicine, Kanagawa Dental University, 82 Inaokacho, Yokosuka 238-8580, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Midori","family":"Katsuyama","sequence":"additional","affiliation":[{"name":"Department of Legal Medicine, Kagoshima University Graduate School of Medicine and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takahisa","family":"Okuda","sequence":"additional","affiliation":[{"name":"Department of Legal Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,28]]},"reference":[{"key":"ref_1","unstructured":"Hall, P. (1995). Alcoholic Liver Disease, Edward Arnold Publishers Ltd.. [2nd ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.livres.2019.09.002","article-title":"Lipid droplet dynamics in alcoholic fatty liver disease","volume":"3","author":"Schulze","year":"2019","journal-title":"Liver Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"748174","DOI":"10.1155\/2009\/748174","article-title":"Peroxisome proliferator-activated receptor and retinoic X receptor in alcoholic liver disease","volume":"2009","author":"Mello","year":"2009","journal-title":"PPAR Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.alcohol.2004.07.008","article-title":"Alcohol fatty liver: Its pathogenesis and mechanism of progression to inflammation and fibrosis","volume":"34","author":"Lieber","year":"2004","journal-title":"Alcohol"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1002\/hep.22222","article-title":"Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice","volume":"47","author":"Lu","year":"2008","journal-title":"Hepatology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.tips.2015.05.001","article-title":"Nitric oxide in liver diseases","volume":"36","author":"Iwakiri","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"G1","DOI":"10.1152\/ajpgi.00056.2004","article-title":"Recent advances in alcoholic liver disease II. Minireview: Molecular mechanisms of alcoholic fatty liver","volume":"287","author":"You","year":"2004","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"G548","DOI":"10.1152\/ajpgi.00342.2011","article-title":"Activation of peroxisome proliferator-activated receptor-\u03b3 by rosiglitazone improves lipid homeostasis at adipose tissue-liver axis in ethanol-fed mice","volume":"302","author":"Sun","year":"2012","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1002\/hep.510290420","article-title":"High-level expression of rat class I alcohol dehydrogenase is sufficient for ethanol-induced fat accumulation in transduced Hela cells","volume":"29","author":"Galli","year":"1999","journal-title":"Hepatology"},{"key":"ref_10","first-page":"649","article-title":"Peroxisome proliferator-activated receptor; nuclear control of metabolism","volume":"20","author":"Desvergne","year":"1999","journal-title":"Endocr. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"29352","DOI":"10.1038\/srep29352","article-title":"Suppression of PPAR\u03b3-mediated monoacylglycerol O-acyltransferase 1 expression ameliorates alcoholic hepatic steatosis","volume":"6","author":"Yu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1111\/acer.13049","article-title":"Hepatic peroxisome proliferation-activated receptor gamma signaling contributes to alcohol-induced hepatic steatosis and inflammation in mice","volume":"40","author":"Zhang","year":"2016","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1172\/JCI73780","article-title":"S-nitrosoglutathione reductase-dependent PPAR\u03b3 denitrosylation participates in MSC-derived adipogenesis and osteogenesis","volume":"125","author":"Cao","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/35068596","article-title":"A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans","volume":"410","author":"Liu","year":"2001","journal-title":"Nature"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/S0092-8674(04)00131-X","article-title":"Essential roles of S-nitrosothiols in vascular homeostasis and endotoxic shock","volume":"116","author":"Liu","year":"2004","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"533","DOI":"10.4062\/biomolther.2018.179","article-title":"Pathophysiological role of S-nitrosylation and transnitrosylation depending on S-nitrosoglutathione levels regulated by S-nitrosoglutathione reductase","volume":"26","author":"Choi","year":"2018","journal-title":"Biomol. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.bbadis.2005.11.008","article-title":"In vivo contribution of Class III alcohol dehydrogenase (ADH3) to alcohol metabolism through activation by cytoplasmic solution hydrophobicity","volume":"1762","author":"Haseba","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/jgh.14260","article-title":"Metabolic pharmacokinetics of chronic alcohol consumption mediated by liver alcohol dehydrogenases 1 and 3 in mice","volume":"33","author":"Okuda","year":"2018","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1093\/alcalc\/agz091","article-title":"Roles of two major alcohol dehydrogenases ADH1 (Class I) and ADH3 (Class III), in the adaptive enhancement of alcohol metabolism induced by chronic alcohol consumption in mice","volume":"55","author":"Haseba","year":"2020","journal-title":"Alcohol Alcohol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1111\/gtc.12237","article-title":"Alcohol dehydrogenase 3 contributes to the protection of liver from nonalcoholic steatohepatitis","volume":"20","author":"Goto","year":"2015","journal-title":"Genes Cells"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.celrep.2013.12.007","article-title":"S-nitrosothiol signaling regulates hepatogenesis and improves outcome following toxic liver injury","volume":"6","author":"Cox","year":"2014","journal-title":"Cell Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1002\/hep.27137","article-title":"Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural cells in mice","volume":"60","author":"Yi","year":"2014","journal-title":"Hepatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"16796","DOI":"10.1074\/jbc.274.24.16796","article-title":"Metabolic deficiencies in alcohol dehydrogenase Adh1, Adh3, and Adh4 null mutant mice. Overlapping roles of Adh1 and Adh4 in ethanol clearance and metabolism of retinol to retinoic acid","volume":"274","author":"Deltour","year":"1999","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.molcel.2015.08.020","article-title":"Endogenous formaldehyde is a hematopoietic stem cell genotoxin and metabolism carcinogen","volume":"60","author":"Pontel","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1080\/10409238.2017.1304353","article-title":"The roles of S-nitrosoglutathione reductase (GSNOR) in human disease and therapy","volume":"52","author":"Barnett","year":"2017","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"145","DOI":"10.2174\/157488407780598135","article-title":"Ethanol metabolism and effects: Nitric oxide and its interaction","volume":"2","author":"Deng","year":"2007","journal-title":"Curr. Clin. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1126\/science.162.3856.917","article-title":"Ethanol oxidation by hepatic microsomes: Adaptive increase after ethanol feeding","volume":"162","author":"Lieber","year":"1968","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13656","DOI":"10.1073\/pnas.1203218109","article-title":"Nuclear receptor PPAR\u03b3-regulated monoacylglycerol O-acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet-induced hepatic steatosis","volume":"109","author":"Lee","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1111\/bcpt.13190","article-title":"A role of peroxisome proliferator-activated receptor \u03b3 in non-alcoholic fatty liver disease","volume":"124","author":"Ipsen","year":"2019","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"E1195","DOI":"10.1152\/ajpendo.00513.2004","article-title":"PPAR2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes","volume":"288","author":"Schadinger","year":"2005","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"199","DOI":"10.2220\/biomedres.12.199","article-title":"Intralobular and intracellular localization of alcohol dehydrogenase (ADH) isozymes in mouse liver: Basic ADH (Class I) and acidic ADH (Class III)","volume":"12","author":"Haseba","year":"1991","journal-title":"Biomed. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1097\/01.alc.0000187597.62590.a4","article-title":"Chronic ethanol exposure stimulates endothelial cell nitric oxide production through PI-3 kinase- and hsp90-dependent mechanisms","volume":"29","author":"Polikandriotis","year":"2006","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/S0016-5085(85)80003-2","article-title":"Oxygen supply to the liver in patients with alcoholic disease assayed by organ-reflectance spectrophotometry","volume":"88","author":"Hayashi","year":"1985","journal-title":"Gasteroenterology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1124\/mol.113.088039","article-title":"Ursodeoxycholyl lysophosphatidylethanolamide inhibits lipoapoptosis by shifting fatty acid pools toward monosaturated and polyunsaturated fatty acids in mouse hepatocytes","volume":"84","author":"Chamulitrat","year":"2013","journal-title":"Mol. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"H1134","DOI":"10.1152\/ajpheart.00887.2012","article-title":"Reduction of cardiomyocyte S-nitrosylation by S-nitrosoglutathione reductase protects against sepsis-induced myocardial depression","volume":"304","author":"Sips","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/12102\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:21:31Z","timestamp":1760127691000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/15\/12102"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,28]]},"references-count":35,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["ijms241512102"],"URL":"https:\/\/doi.org\/10.3390\/ijms241512102","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,28]]}}}