{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:19:34Z","timestamp":1790605174761,"version":"4.1.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2679,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"name":"United State Public Health Service","award":["AA03312"],"award-info":[{"award-number":["AA03312"]}]},{"name":"United State Public Health Service","award":["AA06610"],"award-info":[{"award-number":["AA06610"]}]},{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"crossref","award":["AA015697"],"award-info":[{"award-number":["AA015697"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,5]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:bold>Cytochrome P450 2E1 (CYP2E1) is suggested to play a role in alcoholic liver disease, which includes alcoholic fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. In this study, we investigated whether CYP2E1 plays a role in experimental alcoholic fatty liver in an oral ethanol-feeding model. After 4 weeks of ethanol feeding, macrovesicular fat accumulation and accumulation of triglyceride in liver were observed in wild-type mice but not in CYP2E1-knockout mice. In contrast, free fatty acids (FFAs) were increased in CYP2E1-knockout mice but not in wild-type mice. CYP2E1 was induced by ethanol in wild-type mice, and oxidative stress induced by ethanol was higher in wild-type mice than in CYP2E1-knockout mice. Peroxisome proliferator-activated receptor \u03b1 (PPAR\u03b1), a regulator of fatty acid oxidation, was up-regulated in CYP2E1-knockout mice fed ethanol but not in wild-type mice. A PPAR\u03b1 target gene, acyl CoA oxidase, was decreased by ethanol in wild-type but not in CYP2E1-knockout mice. Chlormethiazole, an inhibitor of CYP2E1, lowered macrovesicular fat accumulation, inhibited oxidative stress, and up-regulated PPAR\u03b1 protein level in wild-type mice fed ethanol. The introduction of CYP2E1 to CYP2E1-knockout mice via an adenovirus restored macrovesicular fat accumulation. These results indicate that CYP2E1 contributes to experimental alcoholic fatty liver in this model and suggest that CYP2E1-derived oxidative stress may inhibit oxidation of fatty acids by preventing up-regulation of PPAR\u03b1 by ethanol, resulting in fatty liver.<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.22222","type":"journal-article","created":{"date-parts":[[2008,2,7]],"date-time":"2008-02-07T10:17:44Z","timestamp":1202379464000},"page":"1483-1494","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":274,"title":["Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice"],"prefix":"10.1097","volume":"47","author":[{"given":"Yongke","family":"Lu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Zhuge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxiang","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur I.","family":"Cederbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-8-20241201","first-page":"707","article-title":"Alcoholic liver disease: morphological manifestation.","volume":"28","author":"Baptista","year":"1981","journal-title":"Lancet"},{"key":"R2-8-20241201","doi-asserted-by":"crossref","first-page":"G881","DOI":"10.1152\/ajpgi.00006.2004","article-title":"Recent advances in alcoholic liver disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease.","volume":"286","author":"Rao","year":"2004","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R3-8-20241201","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1073\/pnas.94.6.2557","article-title":"Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steatohepatitis.","volume":"94","author":"Yang","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R4-8-20241201","doi-asserted-by":"crossref","first-page":"G382","DOI":"10.1152\/ajpgi.2001.281.2.G382","article-title":"Fatty liver vulnerability to endotoxininduced damage despite NFkappaB induction and inhibited caspase 3 activation.","volume":"281","author":"Yang","year":"2001","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R5-8-20241201","doi-asserted-by":"crossref","first-page":"13037","DOI":"10.1074\/jbc.M101632200","article-title":"Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun Nterminal kinase and caspase 3 activation.","volume":"277","author":"Koteish","year":"2002","journal-title":"J Biol Chem"},{"key":"R6-8-20241201","doi-asserted-by":"crossref","first-page":"509","DOI":"10.2174\/1566524033479609","article-title":"CYP2E1: biochemistry, toxicology, regulation and function in ethanolinduced liver injury.","volume":"3","author":"Kessova","year":"2003","journal-title":"Curr Mol Med"},{"key":"R7-8-20241201","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/0024-3205(64)90189-4","article-title":"Prevention of the acute ethanolinduced fatty liver by the simultaneous administration of antioxidants.","volume":"3","author":"Diluzio","year":"1964","journal-title":"Life Sci"},{"key":"R8-8-20241201","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1053\/gast.2001.23253","article-title":"Delivery of the CuZnsuperoxide dismutase gene with adenovirus reduces early alcoholinduced liver injury in rats.","volume":"120","author":"Wheeler","year":"2001","journal-title":"Gastroenterology"},{"key":"R9-8-20241201","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1053\/jhep.2003.50450","article-title":"Alcoholinduced liver injury in mice lacking Cu, Znsuperoxide dismutase.","volume":"38","author":"Kessova","year":"2003","journal-title":"HEPATOLOGY"},{"key":"R10-8-20241201","doi-asserted-by":"crossref","first-page":"1524","DOI":"10.1016\/S0891-5849(01)00741-9","article-title":"Introductionserial review: alcohol, oxidative stress, and cell injury.","volume":"31","author":"Cederbaum","year":"2001","journal-title":"Free Radic Biol Med"},{"key":"R11-8-20241201","doi-asserted-by":"crossref","first-page":"12063","DOI":"10.1074\/jbc.271.20.12063","article-title":"Role of CYP2E1 in the hepatotoxicity of acetaminophen.","volume":"271","author":"Lee","year":"1996","journal-title":"J Biol Chem"},{"key":"R12-8-20241201","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/S0076-6879(94)33061-1","article-title":"Animal models of chronic ethanol toxicity.","volume":"233","author":"Lieber","year":"1994","journal-title":"Methods Enzymol"},{"key":"R13-8-20241201","doi-asserted-by":"crossref","first-page":"G308","DOI":"10.1152\/ajpgi.00054.2005","article-title":"Lipopolysaccharideinduced liver injury in rats treated with the CYP2E1 inducer pyrazole.","volume":"289","author":"Lu","year":"2005","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R14-8-20241201","first-page":"548","article-title":"pNitrophenol hydroxylation. A microsomal oxidation which is highly inducible by ethanol.","volume":"13","author":"Reinke","year":"1985","journal-title":"Drug Metab Dispos"},{"key":"R15-8-20241201","first-page":"795","article-title":"Large scale purification and further characterization of rat pristanoylCoA oxidase, Eur J B","volume":"222","author":"Van Veldhoven","year":"1994","journal-title":"iochem"},{"key":"R16-8-20241201","doi-asserted-by":"crossref","first-page":"27997","DOI":"10.1074\/jbc.M302140200","article-title":"Peroxisome proliferatoractivated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanolfed mice.","volume":"278","author":"Fischer","year":"2003","journal-title":"J Biol Chem"},{"key":"R17-8-20241201","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/sj.bjc.6603360","article-title":"Adipose atrophy in cancer cachexia: morphologic and molecular analysis of adipose tissue in tumourbearing mice.","volume":"95","author":"Bing","year":"2006","journal-title":"Br J Cancer"},{"key":"R18-8-20241201","doi-asserted-by":"crossref","first-page":"7636","DOI":"10.1074\/jbc.M309439200","article-title":"Hypertriglyceridemia in lecithincholesterol acyltransferasedeficient mice is associated with hepatic overproduction of triglycerides, increased lipogenesis, and improved glucose tolerance.","volume":"279","author":"Ng","year":"2004","journal-title":"J Biol Chem"},{"key":"R19-8-20241201","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1023\/B:MCBI.0000038232.61760.9e","article-title":"Adenovirus mediated overexpression of CYP2E1 increases sensitivity of HepG2 cells to acetaminophen induced cytotoxicity.","volume":"262","author":"Bai","year":"2004","journal-title":"Mol Cell Biochem"},{"key":"R20-8-20241201","doi-asserted-by":"crossref","first-page":"29342","DOI":"10.1074\/jbc.M202411200","article-title":"Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory elementbinding protein (SREBP).","volume":"277","author":"You","year":"2002","journal-title":"J Biol Chem"},{"key":"R21-8-20241201","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1053\/j.gastro.2004.09.049","article-title":"The role of AMPactivated protein kinase in the action of ethanol in the liver.","volume":"127","author":"You","year":"2004","journal-title":"Gastroenterology"},{"key":"R22-8-20241201","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/hep.21241","article-title":"Enhancement by pyrazole of lipopolysaccharideinduced liver injury in mice: role of cytochrome P450 2E1 and 2A5.","volume":"44","author":"Lu","year":"2006","journal-title":"HEPATOLOGY"},{"key":"R23-8-20241201","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1093\/toxsci\/kfj165","article-title":"Adenovirusmediated expression of CYP2E1 produces liver toxicity in mice.","volume":"91","author":"Bai","year":"2006","journal-title":"Toxicol Sci"},{"key":"R24-8-20241201","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev.pharmtox.44.101802.121704","article-title":"Oxidative stress, toxicology, and pharmacology of CYP2E1.","volume":"44","author":"Caro","year":"2004","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"R25-8-20241201","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1053\/jhep.2002.30691","article-title":"Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression.","volume":"35","author":"Woodcroft","year":"2002","journal-title":"HEPATOLOGY"},{"key":"R26-8-20241201","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1016\/0024-3205(95)00150-5","article-title":"Hydroxyl radical formation in diabetic rats induced by streptozotocin.","volume":"56","author":"Ohkuwa","year":"1995","journal-title":"Life Sci"},{"key":"R27-8-20241201","first-page":"275","article-title":"Induction of cytochrome P450IIE1 in the obese overfed rat. Mol.","volume":"39","author":"Raucy","year":"1991","journal-title":"Pharmacol"},{"key":"R28-8-20241201","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0006-291X(05)81061-7","article-title":"Transcriptional control of CYP2E1 in the perivenous liver region and during starvation.","volume":"173","author":"Johansson","year":"1990","journal-title":"Biochem Biophys Res Commun"},{"key":"R29-8-20241201","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1021\/bi00406a019","article-title":"Ethanol, fasting, and acetoneinducible cytochromes P450 in rat liver: regulation and characteristics of enzymes belonging to the IIB and IIE gene subfamilies.","volume":"27","author":"Johansson","year":"1988","journal-title":"Biochemistry"},{"key":"R30-8-20241201","first-page":"474","article-title":"Pretranslational activation of cytochrome P450IIE during ketosis induced by a high fat diet.","volume":"41","author":"Yun","year":"1992","journal-title":"Mol Pharmacol"},{"key":"R31-8-20241201","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/S0026-895X(24)13076-3","article-title":"Regulation of rabbit cytochrome P4502E1 expression in HepG2 cells by insulin and thyroid hormone.","volume":"54","author":"Peng","year":"1988","journal-title":"Mol Pharmacol"},{"key":"R32-8-20241201","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1002\/hep.510270121","article-title":"Hepatic cytochrome P450 2E1 is increased in patients with nonalcoholic steatohepatitis.","volume":"27","author":"Weltman","year":"1998","journal-title":"HEPATOLOGY"},{"key":"R33-8-20241201","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/S0168-8278(00)80094-X","article-title":"Kupffer cell inactivation alleviates ethanolinduced steatosis and CYP2E1 induction but not inflammatory responses in rat liver.","volume":"32","author":"Jarvelainen","year":"2000","journal-title":"J Hepatol"},{"key":"R34-8-20241201","first-page":"302","article-title":"Inhibition of ethanolinduced liver disease in the intragastric feeding rat model by chlormethiazole.","volume":"224","author":"Gouillon","year":"2000","journal-title":"Proc Soc Exp Biol Med"},{"key":"R35-8-20241201","first-page":"G1259","article-title":"CYP2E1 is not involved in early alcoholinduced liver injury.","volume":"277","author":"Kono","year":"1999","journal-title":"Am J Physiol"},{"key":"R36-8-20241201","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/S1386-6346(00)00089-9","article-title":"Regulation of peroxisome proliferator activated receptor alphamediated pathways in alcohol fed cytochrome P450 2E1 deficient mice.","volume":"19","author":"Wan","year":"2001","journal-title":"Hepatol Res"},{"key":"R37-8-20241201","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/S0016-5085(99)70354-9","article-title":"Essential role of tumor necrosis factor alpha in alcoholinduced liver injury in mice.","volume":"117","author":"Yin","year":"1999","journal-title":"Gastroenterology"},{"key":"R38-8-20241201","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":"R39-8-20241201","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1002\/hep.21655","article-title":"Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis.","volume":"45","author":"Yamaguchi","year":"2007","journal-title":"HEPATOLOGY"},{"key":"R40-8-20241201","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1152\/physrev.1997.77.2.517","article-title":"Cytochrome P4502E1: its physiological and pathological role.","volume":"77","author":"Lieber","year":"1997","journal-title":"Physiol Rev"},{"key":"R41-8-20241201","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1002\/hep.20532","article-title":"Cytochrome P450 CYP2E1, but not nicotinamide adenine dinucleotide phosphate oxidase, is required for ethanolinduced oxidative DNA damage in rodent liver.","volume":"41","author":"Bradford","year":"2005","journal-title":"HEPATOLOGY"},{"key":"R42-8-20241201","doi-asserted-by":"crossref","first-page":"3022","DOI":"10.1093\/jn\/136.12.3022","article-title":"Systemic oxidative alterations are associated with visceral adiposity and liver steatosis in patients with metabolic syndrome.","volume":"136","author":"Palmieri","year":"2006","journal-title":"J Nutr"},{"key":"R43-8-20241201","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1111\/j.1440-1746.2006.04420.x","article-title":"Increased lipid peroxidation in patients with nonalcoholic fatty liver disease and chronic hepatitis C as measured by the plasma level of 8isoprostane.","volume":"21","author":"Konishi","year":"2006","journal-title":"J Gastroenterol Hepatol"},{"key":"R44-8-20241201","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1097\/01.mcg.0000212608.59090.08","article-title":"Oxidant stress and antioxidant status among patients with nonalcoholic fatty liver disease (NAFLD).","volume":"40","author":"Madan","year":"2006","journal-title":"J Clin Gastroenterol"},{"key":"R45-8-20241201","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1172\/JCI8814","article-title":"CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis.","volume":"105","author":"Leclercq","year":"2000","journal-title":"J Clin Invest"},{"key":"R46-8-20241201","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/S0022-2275(20)33460-X","article-title":"Dietary oxidized fatty acids: an atherogenic risk?","volume":"41","author":"Penumetcha","year":"2000","journal-title":"J Lipid Res"},{"key":"R47-8-20241201","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cld.2004.10.005","article-title":"Metabolism of alcohol.","volume":"9","author":"Lieber","year":"2005","journal-title":"Clin Liver Dis"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.22222","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200805000-00008","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,26]],"date-time":"2025-01-26T23:41:38Z","timestamp":1737934898000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200805000-00008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,5]]},"references-count":47,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2008]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.22222","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2008,5]]}}}