Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease
Open accessAbstract
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.
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Altered mtDNA methylation patterns have been linked to human conditions such as cardiovascular disease, colorectal cancer, non-alcoholic steatohepatitis, obesity-related insulin resistance, and Down syndrome.
“Human diseases, including cardiovascular diseases110, colorectal cancer111, non-alcoholic steatohepatitis112, obesity-induced insulin resistance113 and Down syndrome114, have also been associated with changes in mtDNA methylation patterns.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [112]
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Retracted
- Authors
- Pirola, C. J., Gianotti, T. F., Burgueño, A. L., Rey-Funes, M., Loidl, C. F., Mallardi, P., Martino, J. S., Castaño, G. O., & Sookoian, S.
- Affiliations
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Institute of Cellular Biology and Neuroscience “Prof. E. De Robertis”, School of Medicine, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
- Department of Pathology, Hospital Diego Thompson, San Martin, Buenos Aires, Argentina
- Liver Unit, Medicine and Surgery Department, Hospital Abel Zubizarreta. Ciudad Autónoma de Buenos Aires, Argentina
- Corresponding author
- Pirola, Carlos Jose
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2012-08-09
- Volume
- 62
- Issue
- 9
- Pages
- 1356-1363
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W2106592077
- Cited by
- 364
- References
- 38
- Citations by year
- 2026: 19 · 2025: 26 · 2024: 20 · 2023: 38 · 2022: 26 · 2021: 29 · 2020: 36 · 2019: 28 · 2018: 23 · 2017: 32 · 2016: 31 · 2015: 27 · 2014: 18 · 2013: 10
- FWCI
- 13.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- CONICET Digital (CONICET) (submittedVersion, cc-by-nc-sa)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, mitochondrial DNA, DNA methylation, MT-ND6, MT-CO1, D-loop, histological severity, physical activity, mitochondrial defects, peroxisome proliferation, steatosis
- MeSH terms
- DNA (Cytosine-5-)-Methyltransferase 1, Adult, Biopsy, Cytosine, DNA (Cytosine-5-)-Methyltransferases, DNA, Mitochondrial, Fatty Liver, Female, Humans, Liver, Male, Middle Aged, Mitochondria, Liver, NADH Dehydrogenase, Severity of Illness Index, Transcriptional Activation, Case-Control Studies, Disease Progression, DNA Methylation, Epigenesis, Genetic, Gene-Environment Interaction, Non-alcoholic Fatty Liver Disease
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