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.
- DNA methylation
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Contributors CJP and SS designed the study, analysed and interpreted the data, and prepared and wrote the manuscript. TFG and AB performed molecular experiments. SS and GC collected samples and performed liver biopsies. MRF and CFL performed electron microscopy studies, and PM and JSM performed immunohistochemistry.
Funding Supported in part by Grants UBACYT CM04 (Universidad de Buenos Aires), PICT 2008-1521 and 2010-0441 (Agencia Nacional de Promoción Científica y Tecnológica). SS, TFG, ALB, CFL and CJP belong to Consejo Nacional de Investigaciones Científicas (CONICET). SS and GC belong to Consejo de Investigación en Salud del Gobierno de la Ciudad Autonóma de Bs. As.
Competing interests None.
Ethics approval This study was approved by the Ethical Committee of our institution where patients were recruited (Hospital Abel Zubizarreta. Ciudad AutÃ3noma de Buenos Aires, Argentina).
Provenance and peer review Not commissioned; externally peer reviewed.