title: Wilson's disease: changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease.
abstract: Hepatic methionine metabolism may play an essential role in regulating methylation status and liver injury in Wilson's disease (WD) through the inhibition of S-adenosylhomocysteine hydrolase (SAHH) by copper (Cu) and the consequent accumulation of S-adenosylhomocysteine (SAH). We studied the transcript levels of selected genes related to liver injury, levels of SAHH, SAH, DNA methyltransferases genes (Dnmt1, Dnmt3a, Dnmt3b), and global DNA methylation in the tx-j mouse (tx-j), an animal model of WD. Findings were compared to those in control C3H mice, and in response to Cu chelation by penicillamine (PCA) and dietary supplementation of the methyl donor betaine to modulate inflammatory and methylation status. Transcript levels of selected genes related to endoplasmic reticulum stress, lipid synthesis, and fatty acid oxidation were down-regulated at baseline in tx-j mice, further down-regulated in response to PCA, and showed little to no response to betaine. Hepatic Sahh transcript and protein levels were reduced in tx-j mice with consequent increase of SAH levels. Hepatic Cu accumulation was associated with inflammation, as indicated by histopathology and elevated serum alanine aminotransferase (ALT) and liver tumor necrosis factor alpha (Tnf-α) levels. Dnmt3b was down-regulated in tx-j mice together with global DNA hypomethylation. PCA treatment of tx-j mice reduced Tnf-α and ALT levels, betaine treatment increased S-adenosylmethionine and up-regulated Dnmt3b levels, and both treatments restored global DNA methylation levels.
  
  
  CONCLUSIONS
  Reduced hepatic Sahh expression was associated with increased liver SAH levels in the tx-j model of WD, with consequent global DNA hypomethylation. Increased global DNA methylation was achieved by reducing inflammation by Cu chelation or by providing methyl groups. We propose that increased SAH levels and inflammation affect widespread epigenetic regulation of gene expression in WD.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis, Davis, CA 95817, USA. valentina.medici@ucdmc.ucdavis.edu
authors.forename: Valentina
authors.initials: V
authors.lastname: Medici
authors.forename: Noreene M
authors.initials: NM
authors.lastname: Shibata
authors.forename: Kusum K
authors.initials: KK
authors.lastname: Kharbanda
authors.forename: Janine M
authors.initials: JM
authors.lastname: LaSalle
authors.forename: Rima
authors.initials: R
authors.lastname: Woods
authors.forename: Sarah
authors.initials: S
authors.lastname: Liu
authors.forename: Jesse A
authors.initials: JA
authors.lastname: Engelberg
authors.forename: Sridevi
authors.initials: S
authors.lastname: Devaraj
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Török
authors.forename: Joy X
authors.initials: JX
authors.lastname: Jiang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Havel
authors.forename: Bo
authors.initials: B
authors.lastname: Lönnerdal
authors.forename: Kyoungmi
authors.initials: K
authors.lastname: Kim
authors.forename: Charles H
authors.initials: CH
authors.lastname: Halsted
mesh_terms: D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001622:Betaine / Q000378:metabolism / Q000494:pharmacology; D003300:Copper / Q000378:metabolism / Q000494:pharmacology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004195:Disease Models, Animal; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress; D044127:Epigenesis, Genetic / Q000187:drug effects; D006527:Hepatolenticular Degeneration / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D010396:Penicillamine / Q000494:pharmacology; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D043383:Adenosylhomocysteinase; D001622:Betaine; D003300:Copper; D004248:DNA (Cytosine-5-)-Methyltransferases; D008715:Methionine; D010396:Penicillamine; D012435:S-Adenosylhomocysteine; D000097584:DNA Methyltransferase 3B