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.
Gut. 2013 Sep;62(9):1356-63. doi: 10.1136/gutjnl-2012-302962. Epub 2012 Aug 9.
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.
We studied liver biopsies obtained from patients with NAFLD in a case-control design; 45 patients and 18 near-normal liver-histology subjects.
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.
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.
非酒精性脂肪性肝病（NAFLD）是一种临床病症，其特征为组织学变化逐渐进展，从单纯性脂肪变性（SS）到非酒精性脂肪性肝炎（NASH）。我们评估了肝线粒体 DNA（mtDNA）特定区域（如 D 环调控区、编码 NADH 脱氢酶 6（MT-ND6）和细胞色素 C 氧化酶 I（MT-CO1）的线粒体基因）的胞嘧啶甲基化（5mC）状态，以验证表观遗传修饰在从 SS 向 NASH 表型转变中发挥作用的假说。
我们采用病例对照设计，研究了 NAFLD 患者的肝活检组织；共纳入 45 名 NASH 患者和 18 名接近正常肝组织学的对照者。
NASH 患者肝组织中 MT-ND6 的甲基化水平高于 SS 患者（p < 0.04），且 MT-ND6 甲基化 DNA/未甲基化 DNA 比值与 NAFLD 活动评分显著相关（p < 0.02）。NASH 患者的肝 MT-ND6 mRNA 表达水平（0.26 ± 0.30）显著低于 SS 患者（0.74 ± 0.48）（p < 0.003），蛋白水平也有所降低。NASH 组肝 MT-ND6 甲基化状态与规律体力活动水平呈负相关（R = -0.54，p < 0.02）。D 环和 MT-CO1 的肝甲基化水平与疾病严重程度无关。DNA（胞嘧啶-5）甲基转移酶 1 在 NASH 患者中显著上调（p < 0.002）。超微结构评估显示，NASH 与线粒体缺陷和过氧化物酶体增殖有关。
肝 MT-ND6 的甲基化和转录活性与 NAFLD 的组织学严重程度相关。mtDNA 的表观遗传变化可能通过干预方案逆转，因为体力活动可以调节 MT-ND6 的甲基化状态。
