Ma Chifa, Liu Yiwen, He Shuli, Zeng Jingbo, Li Pingping, Ma Chunxiao, Ping Fan, Zhang Huabing, Xu Lingling, Li Wei, Li Yuxiu
Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Department of Nutrition, Peking Union Medical College Hospital, Beijing, China.
Front Med (Lausanne). 2020 Sep 10;7:536. doi: 10.3389/fmed.2020.00536. eCollection 2020.
Alterations in mitochondrial DNA are potentially associated with oxidative stress and may be involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the association between mitochondrial DNA copy number (mtDNAcn) and NAFLD was not consistent. In addition, the association between inflammation and NAFLD has not been established yet. The present study, based on a Chinese population of individuals with different glucose statuses, aimed to explore the association between leukocyte mtDNAcn, markers of oxidative stress, and inflammation and NAFLD. A total of 318 participants from a diabetes project were included. NAFLD was diagnosed by ultrasonography. Leukocyte mtDNAcn was determined by PCR assay. The levels of the inflammation markers tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) and the oxidative stress markers glutathione reductase (GR), superoxide dismutase (SOD), and 8-oxo-2'-deoxyguanosine (8-oxo-dG) were also measured. Participants with NAFLD ( = 105) exhibited significantly higher leukocyte mtDNAcn, IL-6, and 8-oxo-dG (all < 0.05). Pearson correlation analysis indicated mtDNAcn was negatively associated with age, uric acid, SOD, and TNF-α, but was positively associated with 8-oxo-dG (all < 0.05). Univariate logistic regression analysis revealed that mtDNAcn was positively associated with NAFLD [odds ratio (OR) = 1.617, 95% confidence interval (CI) = 1.036-2.525; = 0.034]. However, after adjustment for 8-oxo-dG, this association was no longer statistically significant (OR = 1.534, 95% CI = 0.979-2.403, = 0.062). Moreover, the stress marker 8-oxo-dG was independently associated with NAFLD after adjustment for mtDNAcn, IL-6, glucose tolerance status, and other conventional NAFLD risk factors (OR = 1.707, 95% CI =1.142-2.550, = 0.009). Mediation analysis indicated that 8-oxo-dG fully mediated the effect of mtDNAcn on the incidence of NAFLD (direct effect β = 0.5221, 95% CI = -0.0648 to 1.2504; indirect effect β = 0.0946, 95% CI = 0.0049-0.2463). In a Chinese population, the association between leukocyte mtDNAcn and NAFLD was fully mediated by high levels of 8-oxo-dG. Thus, oxidative stress may be an important driver of NAFLD, and clinical interventions aimed at decreasing oxidative stress to improve NAFLD warrant further research.
线粒体DNA的改变可能与氧化应激相关，并可能参与非酒精性脂肪性肝病（NAFLD）的发病机制。然而，线粒体DNA拷贝数（mtDNAcn）与NAFLD之间的关联并不一致。此外，炎症与NAFLD之间的关联尚未确立。本研究基于中国不同血糖状态的人群，旨在探讨白细胞mtDNAcn、氧化应激标志物、炎症与NAFLD之间的关联。纳入了来自一个糖尿病项目的318名参与者。通过超声检查诊断NAFLD。通过PCR测定法确定白细胞mtDNAcn。还测量了炎症标志物肿瘤坏死因子α（TNF-α）和白细胞介素6（IL-6）以及氧化应激标志物谷胱甘肽还原酶（GR）、超氧化物歧化酶（SOD）和8-氧代-2'-脱氧鸟苷（8-氧代-dG）的水平。患有NAFLD的参与者（n = 105）表现出显著更高的白细胞mtDNAcn、IL-6和8-氧代-dG（均P < 0.05）。Pearson相关性分析表明，mtDNAcn与年龄、尿酸、SOD和TNF-α呈负相关，但与8-氧代-dG呈正相关（均P < 0.05）。单因素逻辑回归分析显示，mtDNAcn与NAFLD呈正相关[比值比（OR）= 1.617，95%置信区间（CI）= 1.036 - 2.525；P = 0.034]。然而，在对8-氧代-dG进行校正后，这种关联不再具有统计学意义（OR = 1.534，95% CI = 0.979 - 2.403，P = 0.062）。此外，在对mtDNAcn、IL-6、糖耐量状态和其他传统NAFLD危险因素进行校正后，应激标志物8-氧代-dG与NAFLD独立相关（OR = 1.707，95% CI = 1.142 - 2.550，P = 0.009）。中介分析表明，8-氧代-dG完全介导了mtDNAcn对NAFLD发病率的影响（直接效应β = 0.5221，95% CI = -0.0648至1.2504；间接效应β = 0.0946，95% CI = 0.0049 - 0.2463）。在中国人群中，白细胞mtDNAcn与NAFLD之间的关联完全由高水平的8-氧代-dG介导。因此，氧化应激可能是NAFLD的一个重要驱动因素，旨在降低氧化应激以改善NAFLD的临床干预值得进一步研究。
