Artículo
Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease
Pirola, Carlos José
; Fernández Gianotti, Tomás
; Burgueño, Adriana Laura
; Rey Funes, Manuel; Loidl, Cesar Fabian
; Mallardi, Pablo; San Martino, Julio; Castaño, Gustavo Osvaldo; Sookoian, Silvia Cristina
Fecha de publicación:
09/2013
Editorial:
B M J Publishing Group
Revista:
Gut
ISSN:
0017-5749
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Palabras clave:
Epigenetics
,
Mitochondrial Dysfunction
,
Mt-Nd6
,
Nafld
,
Dna Methylation
,
Nash
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Articulos(IBCN)
Articulos de INST.DE BIOLO.CEL.Y NEURCS."PROF.E.DE ROBERTIS"
Articulos de INST.DE BIOLO.CEL.Y NEURCS."PROF.E.DE ROBERTIS"
Articulos(IDIM)
Articulos de INST.DE INVEST.MEDICAS
Articulos de INST.DE INVEST.MEDICAS
Citación
Pirola, Carlos José; Fernández Gianotti, Tomás; Burgueño, Adriana Laura; Rey Funes, Manuel; Loidl, Cesar Fabian; et al.; Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease; B M J Publishing Group; Gut; 62; 9; 9-2013; 1356-1363
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