{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:05:09Z","timestamp":1791194709465,"version":"4.1.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2740,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,3]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Although recent evidence suggests that down-regulation of production of the adipocyte hormone adiponectin has pathophysiological consequences for the development of alcoholic liver disease (ALD), the underlying mechanisms are elusive. Abnormal hepatic methionine-homocysteine metabolism induced by prolonged alcohol exposure has been reported both in clinical and experimental studies of ALD. Here, we conducted both in vivo and in vitro experiments to examine the effects of prolonged alcohol exposure on homocysteine levels in adipose tissue, its potential involvement in regulating adiponectin production, and the consequences for ALD. Chronic alcohol exposure decreased the circulating adiponectin concentration and adiponectin messenger RNA (mRNA) and protein levels in epididymal fat pads. Alcohol feeding induced modest hyperhomocysteinemia and increased homocysteine levels in the epididymal fat pad, which was associated with decreased mRNA levels of cystationine \u03b2-synthase. Betaine supplementation (1.5%, wt\/vol) in the alcohol-fed mice reduced homocysteine accumulation in adipose tissue and improved adiponectin levels. Moreover, exogenous homocysteine administration reduced gene expression, protein levels, and secretion of adiponectin in primary adipocytes. Furthermore, rats fed a high-methionine diet (2%, wt\/wt) were hyperhomocysteinemic and had decreased adiponectin levels in both plasma and adipose tissue, which was associated with suppressed AMP-activated protein kinase activation in the liver. Mechanistic studies revealed that both inactivation of the extracellular signal regulated kinase 1\/2 pathway and induction of endoplasmic reticulum stress response, specifically C\/EBP homologous protein expression, may contribute to the inhibitory effect exerted by homocysteine.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion:\n                                 <\/jats:bold>\n                                 <jats:bold>Chronic alcohol feeding caused abnormal accumulation of homocysteine in adipocytes, which contributes to decreased adiponectin production in ALD.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.22074","type":"journal-article","created":{"date-parts":[[2007,12,31]],"date-time":"2007-12-31T23:46:49Z","timestamp":1199144809000},"page":"867-879","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":104,"title":["Inhibition of adiponectin production by homocysteine: A potential mechanism for alcoholic liver disease"],"prefix":"10.1097","volume":"47","author":[{"given":"Zhenyuan","family":"Song","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanxiang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ion","family":"Deaciuc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig J.","family":"McClain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-13-20241201","first-page":"321","article-title":"Liver damage in chronic alcoholism. Results of a clinical, clinicalchemical and bioptichistological study in 526 alcoholic patients during a lowcalorie diet in an open drinking sanatorium.","volume":"13","author":"Lelbach","year":"1966","journal-title":"Acta Hepatosplenol"},{"key":"R2-13-20241201","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/S0741-8329(02)00204-5","article-title":"Liver disease in alcohol abusers: clinical perspective.","volume":"27","author":"Diehl","year":"2002","journal-title":"Alcohol"},{"key":"R3-13-20241201","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":"R4-13-20241201","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":"R5-13-20241201","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":"R6-13-20241201","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.jhep.2006.05.009","article-title":"Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model.","volume":"45","author":"Ji","year":"2006","journal-title":"J Hepatol"},{"key":"R7-13-20241201","doi-asserted-by":"crossref","first-page":"E621","DOI":"10.1152\/ajpendo.00387.2006","article-title":"Chronic ethanol feeding to rats decreases adiponectin secretion by subcutaneous adipocytes.","volume":"292","author":"Chen","year":"2007","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"R8-13-20241201","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1172\/JCI200317797","article-title":"The fatderived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice.","volume":"112","author":"Xu","year":"2003","journal-title":"J Clin Invest"},{"key":"R9-13-20241201","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1002\/hep.20821","article-title":"Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice.","volume":"42","author":"You","year":"2005","journal-title":"HEPATOLOGY"},{"key":"R10-13-20241201","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/0016-5085(81)90489-3","article-title":"Evidence for impairment of transsulfuration pathway in cirrhosis.","volume":"81","author":"Horowitz","year":"1981","journal-title":"Gastroenterol"},{"key":"R12-13-20241201","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1016\/S0016-5085(03)00276-2","article-title":"Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcoholfed mice.","volume":"124","author":"Ji","year":"2003","journal-title":"Gastroenterology"},{"key":"R13-13-20241201","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1016\/j.bcp.2005.09.021","article-title":"2nd, Mailliard ME, Siford GL, Barak AJ, Beckenhauer HC, et al. Role of elevated Sadenosylhomocysteine in rat hepatocyte apoptosis: protection by betaine.","volume":"70","author":"Kharbanda","year":"2005","journal-title":"Biochem Pharmacol"},{"key":"R14-13-20241201","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1002\/hep.20412","article-title":"Sadenosylhomocysteine sensitizes to TNFalpha hepatotoxicity in mice and liver cells: a possible etiological factor in alcoholic liver disease.","volume":"40","author":"Song","year":"2004","journal-title":"HEPATOLOGY"},{"key":"R15-13-20241201","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1002\/hep.510230314","article-title":"Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation.","volume":"23","author":"Halsted","year":"1996","journal-title":"HEPATOLOGY"},{"key":"R16-13-20241201","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1172\/JCI29126","article-title":"Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.","volume":"116","author":"Kadowaki","year":"2006","journal-title":"J Clin Invest"},{"key":"R17-13-20241201","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1079\/PNS2004403","article-title":"Obesity and metabolic disease: is adipose tissue the culprit?","volume":"64","author":"Frayn","year":"2005","journal-title":"Proc Nutr Soc"},{"key":"R18-13-20241201","first-page":"4113","article-title":"Interleukin 6 reduces lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3-L1 adipocytes: a possible role for interleukin 6 in cancer cachexia.","volume":"52","author":"Greenberg","year":"1992","journal-title":"Cancer Res"},{"key":"R19-13-20241201","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0304-4165(02)00148-4","article-title":"Effects of interleukin15 (IL15) on adipose tissue mass in rodent obesity models: evidence for direct IL15 action on adipose tissue.","volume":"1570","author":"Alvarez","year":"2002","journal-title":"Biochim Biophys Acta"},{"key":"R20-13-20241201","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1194\/jlr.D600005-JLR200","article-title":"Optimized conditions for measuring lipolysis in murine primary adipocytes.","volume":"47","author":"Viswanadha","year":"2006","journal-title":"J Lipid Res"},{"key":"R21-13-20241201","first-page":"983","article-title":"Ethanol dependence and tolerance: a nutritionally controlled experimental model in the rat.","volume":"6","author":"Lieber","year":"1973","journal-title":"Res Commun Chem Pathol Pharmacol"},{"key":"R22-13-20241201","doi-asserted-by":"crossref","first-page":"E1002","DOI":"10.1152\/ajpendo.00518.2004","article-title":"Hyperhomocysteinemia induces hepatic cholesterol biosynthesis and lipid accumulation via activation of transcription factors.","volume":"288","author":"Woo","year":"2005","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"R23-13-20241201","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.metabol.2004.12.008","article-title":"Rosiglitazone reduces serum homocysteine levels, smooth muscle proliferation, and intimal hyperplasia in SpragueDawley rats fed a high methionine diet.","volume":"54","author":"Murthy","year":"2005","journal-title":"Metabolism"},{"key":"R24-13-20241201","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1111\/j.1463-1326.2005.00510.x","article-title":"Adiponectina key adipokine in the metabolic syndrome.","volume":"8","author":"Whitehead","year":"2006","journal-title":"Diabetes Obes Metab"},{"key":"R25-13-20241201","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1002\/hep.20708","article-title":"Homocysteine, the bad thiol.","volume":"41","author":"Mato","year":"2005","journal-title":"HEPATOLOGY"},{"key":"R26-13-20241201","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.2337\/diabetes.52.7.1655","article-title":"Induction of adiponectin, a fatderived antidiabetic and antiatherogenic factor, by nuclear receptors.","volume":"52","author":"Iwaki","year":"2003","journal-title":"Diabetes"},{"key":"R27-13-20241201","doi-asserted-by":"crossref","first-page":"2757","DOI":"10.2337\/diabetes.53.11.2757","article-title":"CCAATenhancer binding protein and nuclear factorY regulate adiponectin gene expression in adipose tissue.","volume":"53","author":"Park","year":"2004","journal-title":"Diabetes"},{"key":"R28-13-20241201","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.2337\/diabetes.54.6.1744","article-title":"CEBP regulates human adiponectin gene transcription through an intronic enhancer.","volume":"54","author":"Qiao","year":"2005","journal-title":"Diabetes"},{"key":"R29-13-20241201","doi-asserted-by":"crossref","first-page":"22108","DOI":"10.1074\/jbc.M400238200","article-title":"Adipocyte determination and differentiationdependent factor 1sterol regulatory elementbinding protein 1c regulates mouse adiponectin expression.","volume":"279","author":"Seo","year":"2004","journal-title":"J Biol Chem"},{"key":"R30-13-20241201","doi-asserted-by":"crossref","first-page":"901","DOI":"10.2337\/db06-0911","article-title":"Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation.","volume":"56","author":"Hosogai","year":"2007","journal-title":"Diabetes"},{"key":"R31-13-20241201","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.2337\/db06-1300","article-title":"Uncoupling protein2 controls adiponectin gene expression in adipose tissue through the modulation of reactive oxygen species production.","volume":"56","author":"Chevillotte","year":"2007","journal-title":"Diabetes"},{"key":"R32-13-20241201","doi-asserted-by":"crossref","first-page":"46226","DOI":"10.1074\/jbc.M207776200","article-title":"Activation of MEKERK signaling promotes adipogenesis by enhancing peroxisome proliferatoractivated receptor (PPAR) and CEBP gene expression during the differentiation of 3T3-L1 preadipocytes.","volume":"277","author":"Prusty","year":"2002","journal-title":"J Biol Chem"},{"key":"R33-13-20241201","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1002\/j.1460-2075.1995.tb07046.x","article-title":"Requirement of MAP kinase for differentiation of fibroblasts to adipocytes, for insulin activation of p90 S6 kinase and for insulin or serum stimulation of DNA synthesis.","volume":"14","author":"Sale","year":"1996","journal-title":"EMBO J"},{"key":"R34-13-20241201","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.biochi.2004.10.018","article-title":"The role of MAPKs in adipocyte differentiation and obesity.","volume":"87","author":"Bost","year":"2005","journal-title":"Biochimie (Paris)"},{"key":"R35-13-20241201","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/j.neuroscience.2005.03.034","article-title":"Regulation of extracellular signalregulated kinase by homocysteine in hippocampus.","volume":"133","author":"Robert","year":"2005","journal-title":"Neuroscience"},{"key":"R36-13-20241201","doi-asserted-by":"crossref","first-page":"e126","DOI":"10.1161\/01.ATV.0000225290.10643.ea","article-title":"Inhibition of extracellular signalregulated kinase in liver of hyperhomocysteinemic mice.","volume":"26","author":"Hamelet","year":"2006","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"R37-13-20241201","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.jhep.2006.08.024","article-title":"Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway.","volume":"46","author":"Kharbanda","year":"2007","journal-title":"J Hepatol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.22074","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-200803000-00013","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,1]],"date-time":"2024-12-01T13:15:58Z","timestamp":1733058958000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-200803000-00013"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,3]]},"references-count":36,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2008]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.22074","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2008,3]]}}}