Department of Biochemistry, Center for Cellular and Molecular Therapy, Universidade Federal de São Paulo, São Paulo, Brazil.
Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
Am J Physiol Gastrointest Liver Physiol. 2020 Sep 1;319(3):G400-G411. doi: 10.1152/ajpgi.00121.2020. Epub 2020 Jun 29.
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease worldwide. NAFLD is tightly linked to the metabolic syndrome, insulin resistance, and oxidative stress. Globally, its inflammatory form, nonalcoholic steatohepatitis (NASH), has become the main cause of liver-related morbidity and mortality, mainly due to liver cirrhosis and primary liver cancer. One hallmark of NASH is the presence of changes in mitochondrial morphology and function that are accompanied by a blocked flow of electrons in the respiratory chain, which increases formation of mitochondrial reactive oxygen species in a self-perpetuating vicious cycle. Consequences are oxidation of DNA bases and mitochondrial DNA depletion that are coupled with genetic and acquired mitochondrial DNA mutations, all impairing the resynthesis of respiratory chain polypeptides. In general, several maladaptations of pathways that usually maintain energy homeostasis occur with the early and late excess metabolic stress in NAFLD and NASH. We discuss the interplay between hepatocyte mitochondrial stress and inflammatory responses, focusing primarily on events initiated and maintained by mitochondrial free radical-induced damage in NAFLD. Importantly, mitochondrial oxidative stress and dysfunction are modulated by key pharmacological targets that are related to excess production of reactive oxygen species, mitochondrial turnover and the mitochondrial unfolded protein response, mitophagy, and mitochondrial biogenesis. However, the efficacy of such interventions depends on NAFLD/NASH disease stage.
非酒精性脂肪性肝病 (NAFLD) 已成为全球最常见的肝脏疾病。NAFLD 与代谢综合征、胰岛素抵抗和氧化应激密切相关。在全球范围内，其炎症形式——非酒精性脂肪性肝炎 (NASH)——已成为与肝脏相关发病率和死亡率的主要原因，主要是由于肝硬化和原发性肝癌。NASH 的一个标志是线粒体形态和功能的变化，伴随着呼吸链中电子流的阻塞，这会导致线粒体活性氧的形成增加，从而形成自我维持的恶性循环。其后果是氧化 DNA 碱基和线粒体 DNA 耗竭，这与遗传和获得性线粒体 DNA 突变有关，所有这些都会损害呼吸链多肽的重新合成。一般来说，NAFLD 和 NASH 中早期和晚期过度代谢应激会导致维持能量稳态的途径发生几种适应性改变。我们讨论了肝细胞线粒体应激与炎症反应之间的相互作用，主要集中在由线粒体自由基诱导损伤引发和维持的事件上。重要的是，线粒体氧化应激和功能障碍可通过与活性氧过度产生、线粒体周转和线粒体未折叠蛋白反应、线粒体自噬和线粒体生物发生相关的关键药理靶点进行调节。然而，这些干预措施的疗效取决于 NAFLD/NASH 疾病阶段。
