Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China; Institute of Model Animals of Wuhan University, Wuhan, 430072, PR China.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China; Institute of Model Animals of Wuhan University, Wuhan, 430072, PR China; Basic Medical School, Wuhan University, Wuhan, 430071, PR China; Medical Research Institute, School of Medicine, Wuhan University, Wuhan, 430071, PR China.
Free Radic Biol Med. 2020 May 20;152:116-141. doi: 10.1016/j.freeradbiomed.2020.02.025. Epub 2020 Mar 8.
Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide and is strongly associated with the presence of oxidative stress. Disturbances in lipid metabolism lead to hepatic lipid accumulation, which affects different reactive oxygen species (ROS) generators, including mitochondria, endoplasmic reticulum, and NADPH oxidase. Mitochondrial function adapts to NAFLD mainly through the downregulation of the electron transport chain (ETC) and the preserved or enhanced capacity of mitochondrial fatty acid oxidation, which stimulates ROS overproduction within different ETC components upstream of cytochrome c oxidase. However, non-ETC sources of ROS, in particular, fatty acid β-oxidation, appear to produce more ROS in hepatic metabolic diseases. Endoplasmic reticulum stress and NADPH oxidase alterations are also associated with NAFLD, but the degree of their contribution to oxidative stress in NAFLD remains unclear. Increased ROS generation induces changes in insulin sensitivity and in the expression and activity of key enzymes involved in lipid metabolism. Moreover, the interaction between redox signaling and innate immune signaling forms a complex network that regulates inflammatory responses. Based on the mechanistic view described above, this review summarizes the mechanisms that may account for the excessive production of ROS, the potential mechanistic roles of ROS that drive NAFLD progression, and therapeutic interventions that are related to oxidative stress.
非酒精性脂肪性肝病（NAFLD）已成为全球最常见的慢性肝病，与氧化应激密切相关。脂质代谢紊乱导致肝脂质堆积，影响不同的活性氧（ROS）生成器，包括线粒体、内质网和 NADPH 氧化酶。线粒体功能主要通过电子传递链（ETC）的下调和线粒体脂肪酸氧化能力的保留或增强来适应 NAFLD，这会刺激细胞色素 c 氧化酶上游不同 ETC 成分内的 ROS 过度产生。然而，ROS 的非 ETC 来源，特别是脂肪酸β氧化，似乎在肝代谢疾病中产生更多的 ROS。内质网应激和 NADPH 氧化酶改变也与 NAFLD 相关，但它们对 NAFLD 中氧化应激的贡献程度尚不清楚。ROS 生成增加会引起胰岛素敏感性的变化，以及参与脂质代谢的关键酶的表达和活性的变化。此外，氧化还原信号和固有免疫信号之间的相互作用形成了一个复杂的网络，调节炎症反应。基于上述机制观点，本综述总结了可能导致 ROS 过度产生的机制、ROS 驱动 NAFLD 进展的潜在机制作用，以及与氧化应激相关的治疗干预措施。
