Review Article Nonalcoholic Fatty Liver Disease: Pathogenesis and Therapeutics from a Mitochondria-centric Perspective
Review Article Nonalcoholic Fatty Liver Disease: Pathogenesis and Therapeutics from a Mitochondria-centric Perspective
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通讯作者：
A. Gusdon;Ke-xiu Song;S. Qu;Liang-Jun Yan
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作者：
A. Gusdon;Ke-xiu Song;S. Qu;Liang-Jun Yan
非酒精性脂肪性肝病（NAFLD）描述了一系列以甘油三酯在肝脏内积累为特征的疾病。全球NAFLD的患病率一直在增加，因为肥胖流行病没有显示出缓和的迹象。线粒体在肝脏脂质代谢中起核心作用，并且还受到参与肝脏代谢的上游信号通路的影响。本文将重点介绍线粒体在NAFLD病理生理学中的作用，并探讨一些针对线粒体和代谢重要信号通路的治疗方法。线粒体能够通过增加β-氧化速率来适应肝细胞中的脂质蓄积;然而，向线粒体电子传递链（ETC）的底物递送增加导致活性氧（ROS）产生增加，最终导致ETC功能障碍。降低的ETC功能结合增加的脂肪酸β-氧化速率导致β-氧化的不完全产物的积累，其结合增加的ROS水平促成胰岛素抵抗。几种相关的信号通路、核受体和转录因子也调节肝脏脂质代谢，其中许多是氧化还原敏感的并受ROS调节。
Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of disorders characterized by the accumulation of triglycerides within the liver. The global prevalence of NAFLD has been increasing as the obesity epidemic shows no sign of relenting. Mitochondria play a central role in hepatic lipid metabolism and also are affected by upstream signaling pathways involved in hepatic metabolism. This review will focus on the role of mitochondria in the pathophysiology of NAFLD and touch on some of the therapeutic approaches targeting mitochondria as well as metabolically important signaling pathways. Mitochondria are able to adapt to lipid accumulation in hepatocytes by increasing rates of beta-oxidation; however increased substrate delivery to the mitochondrial electron transport chain (ETC) leads to increased reactive oxygen species (ROS) production and eventually ETC dysfunction. Decreased ETC function combined with increased rates of fatty acid beta-oxidation leads to the accumulation of incomplete products of beta-oxidation, which combined with increased levels of ROS contribute to insulin resistance. Several related signaling pathways, nuclear receptors, and transcription factors also regulate hepatic lipid metabolism, many of which are redox sensitive and regulated by ROS.