title: Inhibition of adiponectin production by homocysteine: a potential mechanism for alcoholic liver disease.
abstract: 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 beta-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.
  
  
  CONCLUSIONS
  Chronic alcohol feeding caused abnormal accumulation of homocysteine in adipocytes, which contributes to decreased adiponectin production in ALD.
authors.affiliation: Department of Medicine, University of Louisville, Louisville, KY, USA. z0song02@louisville.edu
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Song
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
authors.forename: Ion
authors.initials: I
authors.lastname: Deaciuc
authors.forename: Theresa
authors.initials: T
authors.lastname: Chen
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
mesh_terms: D052242:Adiponectin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001622:Betaine / Q000008:administration & dosage; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D006710:Homocysteine / Q000032:analysis / Q000378:metabolism*; D020138:Hyperhomocysteinemia / Q000139:chemically induced* / Q000150:complications / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000209:etiology* / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D052242:Adiponectin; D006710:Homocysteine; D000431:Ethanol; D001622:Betaine; D008715:Methionine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003541:Cystathionine beta-Synthase