title: Chronic Alcohol Exposure Differentially Alters One-Carbon Metabolism in Rat Liver and Brain.
abstract: BACKGROUND
  Epigenetic mechanisms such as DNA methylation play an important role in regulating the pathophysiology of alcoholism. Chronic alcohol exposure leads to behavioral changes as well as decreased expression of genes associated with synaptic plasticity. In the liver, it has been documented that chronic alcohol exposure impairs methionine synthase (Ms) activity leading to a decrease in S-adenosyl methionine/S-adenosyl homocysteine (SAM/SAH) ratio which results in DNA hypomethylation; however, it is not known whether similar alterations of SAM and SAH levels are also produced in brain.
  
  
  METHODS
  Male adult Sprague Dawley rats were fed chronically with Lieber-DeCarli ethanol (EtOH) (9% v/v) or control diet. The EtOH-diet-fed rats were withdrawn for 0 and 24 hours. The cerebellum and liver tissues were dissected and used to investigate changes in one-carbon metabolism, SAM, and SAH levels.
  
  
  RESULTS
  We found that chronic EtOH exposure decreased SAM levels, SAM/SAH ratio, Ms, methylene tetrahydrofolate reductase, and betaine homocysteine methyltransferase (Bhmt) expression and increased methionine adenosyltransferase-2b (Mat2b) but not Mat2a expression in the liver. In contrast, chronic EtOH exposure decreased SAH levels, increased SAM/SAH ratio and the expression of Mat2a and S-adenosyl homocysteine hydrolase, while the levels of SAM or Bhmt expression in cerebellum remained unaltered. However, in both liver and cerebellum, chronic EtOH exposure decreased the expression of Ms and increased Mat2b expression. All chronic EtOH-induced changes of one-carbon metabolism in cerebellum, but not liver, returned to near-normal levels during EtOH withdrawal.
  
  
  CONCLUSIONS
  These results indicate a decreased "methylation index" in liver and an increased "methylation index" in cerebellum. The opposing changes of the "methylation index" suggest altered DNA methylation in liver and cerebellum, thus implicating one-carbon metabolism in the pathophysiology of alcoholism.
authors.affiliation: Center for Alcohol Research in Epigenetics , Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: James
authors.identifier: http://orcid.org/0000-0002-5468-7704
authors.initials: J
authors.lastname: Auta
authors.affiliation: Center for Alcohol Research in Epigenetics , Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Huaibo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center for Alcohol Research in Epigenetics , Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.|Jesse Brown VA Medical Center , Chicago, Illinois.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Pandey
authors.affiliation: Center for Alcohol Research in Epigenetics , Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Guidotti
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002244:Carbon / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D019875:One-Carbon Group Transferases / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism
chemical_list: D000431:Ethanol; D002244:Carbon; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D019875:One-Carbon Group Transferases
keywords: Alcohol Dependence; Brain; DNA Methylation; Liver; Methionine Metabolism