Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease

• Published in: Gut Vol. 62; no. 9; pp. 1356 - 1363
• Main Authors: Pirola, Carlos Jose, Gianotti, Tomas Fernández, Burgueño, Adriana Laura, Rey-Funes, Manuel, Loidl, Cesar Fabian, Mallardi, Pablo, Martino, Julio San, Castaño, Gustavo Osvaldo, Sookoian, S
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.09.2013; BMJ Publishing Group LTD
• Subjects: Adult; Biopsy; Case-Control Studies; Cytosine - metabolism; Disease Progression; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA methylation; DNA Methylation - genetics; DNA, Mitochondrial; Epigenesis, Genetic; Epigenetics; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - pathology; Fatty Liver - physiopathology; Female; Gene-Environment Interaction; Humans; Liver; Liver - metabolism; Liver - pathology; Male; Middle Aged; mitochondria; Mitochondria, Liver - genetics; Mitochondria, Liver - metabolism; Mitochondrial DNA; MT-ND6; NADH Dehydrogenase - genetics; NAFLD; Non-alcoholic Fatty Liver Disease; Severity of Illness Index; Transcriptional Activation - genetics; MT-ND6; DNA methylation; NAFLD; mitochondria; epigenetics
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2012-302962

Objective & design 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. Conclusion 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.