title: Rectification of impaired adipose tissue methylation status and lipolytic response contributes to hepatoprotective effect of betaine in a mouse model of alcoholic liver disease.
abstract: OBJECTIVE
  Overactive lipolysis in adipose tissue contributes to the pathogenesis of alcoholic liver disease (ALD); however, the mechanisms involved have not been elucidated. We previously reported that chronic alcohol consumption produces a hypomethylation state in adipose tissue. In this study we investigated the role of hypomethylation in adipose tissue in alcohol-induced lipolysis and whether its correction contributes to the well-established hepatoprotective effect of betaine in ALD.
  
  
  METHODS
  Male C57BL/6 mice were divided into four groups and started on one of four treatments for 5 weeks: isocaloric pair-fed (PF), alcohol-fed (AF), PF supplemented with betaine (BT/AF) and AF supplemented with betaine (BT/AF). Betaine, 0.5% (w v(-1) ), was added to the liquid diet. Both primary adipocytes and mature 3T3-L1 adipocytes were exposed to demethylation reagents and their lipolytic responses determined.
  
  
  RESULTS
  Betaine alleviated alcohol-induced pathological changes in the liver and rectified the impaired methylation status in adipose tissue, concomitant with attenuating lipolysis. In adipocytes, inducing hypomethylation activated lipolysis through a mechanism involving suppression of protein phosphatase 2A (PP2A), due to hypomethylation of its catalytic subunit, leading to increased activation of hormone-sensitive lipase (HSL). In line with in vitro observations, reduced PP2A catalytic subunit methylation and activity, and enhanced HSL activation, were observed in adipose tissue of alcohol-fed mice. Betaine attenuated this alcohol-induced PP2A suppression and HSL activation.
  
  
  CONCLUSIONS
  In adipose tissue, a hypomethylation state contributes to its alcohol-induced dysfunction and an improvement in its function may contribute to the hepatoprotective effects of betaine in ALD.
authors.affiliation: College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China; Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Dou
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Xia
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Qian
authors.forename: Songtao
authors.initials: S
authors.lastname: Li
authors.forename: Ximei
authors.initials: X
authors.lastname: Zhang
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Song
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001622:Betaine / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects*; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D006801:Humans; D008066:Lipolysis / Q000187:drug effects; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D001622:Betaine
keywords: HSL; PP2A; S-adenosylhomocysteine; S-adenosylmethionine; methionine