title: Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease.
abstract: OBJECTIVE
  Nonalcoholic fatty liver disease (NAFLD) is a clinical condition that refers to progressive histological changes ranging from simple steatosis (SS) to nonalcoholic steatohepatitis (NASH). We evaluated the status of cytosine methylation (5mC) of liver mitochondrial DNA (mtDNA) in selected regions of the mtDNA genome, such as D-loop control region, and mitochondrially encoded NADH dehydrogenase 6 (MT-ND6) and cytochrome C oxidase I (MT-CO1), to contrast the hypothesis that epigenetic modifications play a role in the phenotypic switching from SS to NASH.
  
  
  METHODS
  We studied liver biopsies obtained from patients with NAFLD in a case-control design; 45 patients and 18 near-normal liver-histology subjects.
  
  
  RESULTS
  MT-ND6 methylation was higher in the liver of NASH than SS patients (p < 0.04) and MT-ND6 methylated DNA/unmethylated DNA ratio was significantly associated with NAFLD activity score (p < 0.02). Liver MT-ND6 mRNA expression was significantly decreased in NASH patients (0.26 ± 0.30) versus SS (0.74 ± 0.48), p < 0.003, and the protein level was also diminished. The status of liver MT-ND6 methylation in NASH group was inversely correlated with the level of regular physical activity (R = -0.54, p < 0.02). Hepatic methylation levels of D-Loop and MT-CO1 were not associated with the disease severity. DNA (cytosine-5) methyltransferase 1 was significantly upregulated in NASH patients (p < 0.002). Ultrastructural evaluation showed that NASH is associated with mitochondrial defects and peroxisome proliferation.
  
  
  CONCLUSIONS
  Hepatic methylation and transcriptional activity of the MT-ND6 are associated with the histological severity of NAFLD. Epigenetic changes of mtDNA are potentially reversible by interventional programs, as physical activity could modulate the methylation status of MT-ND6.
authors.affiliation: Department of Molecular Genetics and Biology of the Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina. carlos@lanari.fmed.uba.ar
authors.forename: Carlos Jose
authors.initials: CJ
authors.lastname: Pirola
authors.forename: Tomas Fernández
authors.initials: TF
authors.lastname: Gianotti
authors.forename: Adriana Laura
authors.initials: AL
authors.lastname: Burgueño
authors.forename: Manuel
authors.initials: M
authors.lastname: Rey-Funes
authors.forename: Cesar Fabian
authors.initials: CF
authors.lastname: Loidl
authors.forename: Pablo
authors.initials: P
authors.lastname: Mallardi
authors.forename: Julio San
authors.initials: JS
authors.lastname: Martino
authors.forename: Gustavo Osvaldo
authors.initials: GO
authors.lastname: Castaño
authors.forename: S
authors.initials: S
authors.lastname: Sookoian
mesh_terms: D000328:Adult; D001706:Biopsy; D016022:Case-Control Studies; D003596:Cytosine / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D004272:DNA, Mitochondrial; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D059647:Gene-Environment Interaction; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism; D009245:NADH Dehydrogenase / Q000235:genetics*; D065626:Non-alcoholic Fatty Liver Disease; D012720:Severity of Illness Index; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D003596:Cytosine; C507225:MT-ND6 protein, human; D009245:NADH Dehydrogenase; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human