Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.
J Cell Biochem. 2022 Oct;123(10):1585-1606. doi: 10.1002/jcb.30247. Epub 2022 May 1.
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation in the absence of excessive alcohol consumption and is strongly associated with obesity, type 2 diabetes (T2DM) and other metabolic syndrome features. NAFLD is becoming increasingly prevalent and currently constitutes the leading cause of hepatocellular carcinoma (HCC). Recently, the term metabolic (dysfunction) associated fatty liver disease (MAFLD) has been proposed reflecting more accurately the underlying pathogenesis and the cardiometabolic disorders associated to NAFLD/MAFLD. Given the vital metabolic functions of the liver to maintain the body homeostasis, an extended endoplasmic reticulum (ER) network is mandatory in hepatocytes to retain its capacity to adapt to the multiple extracellular and intracellular signals mediating metabolic changes. Dysfunction of hepatocyte ER homeostasis and disturbance of its interaction with mitochondria have been recognized to be involved in the NAFLD pathophysiology. Apart from hepatocytes, hepatic stellate cells, and Kupffer cells have been shown to play an important role in the occurrence of NAFLD and progression to nonalcoholic steatohepatitis (NASH) with possibly different roles in the different stages of the NAFLD spectrum. Furthermore, excess lipid accumulation in the liver causes lipotoxicity which interacts with ER stress and culminates in inflammation and hepatocellular damage, mechanisms crucially implicated in NASH pathogenesis. Finally, the circadian clock machinery regulates ER stress-related pathways and vice versa, thus controlling the homeostasis of the liver metabolism and being implicated in the NAFLD progression. This review presents a comprehensive overview of the current knowledge supporting the impact of ER stress signaling on NAFLD, whilst summarizing potential therapeutic interventions targeting this process.
非酒精性脂肪性肝病（NAFLD）的特征是肝脏脂肪堆积，不存在过量饮酒，并且与肥胖、2 型糖尿病（T2DM）和其他代谢综合征特征密切相关。NAFLD 的发病率越来越高，目前已成为肝细胞癌（HCC）的主要原因。最近，提出了代谢（功能障碍）相关脂肪性肝病（MAFLD）一词，更准确地反映了潜在的发病机制以及与 NAFLD/MAFLD 相关的心脏代谢紊乱。鉴于肝脏对维持身体内环境稳定的重要代谢功能，肝细胞内需要扩展内质网（ER）网络，以保持其适应介导代谢变化的多种细胞外和细胞内信号的能力。已经认识到肝细胞 ER 稳态功能障碍和与线粒体相互作用的紊乱与 NAFLD 的病理生理学有关。除了肝细胞，肝星状细胞和枯否细胞也被证明在 NAFLD 的发生和进展为非酒精性脂肪性肝炎（NASH）中起重要作用，并且在 NAFLD 谱的不同阶段可能具有不同的作用。此外，肝脏中过多的脂质积累会导致脂毒性，脂毒性与 ER 应激相互作用，最终导致炎症和肝细胞损伤，这些机制在 NASH 的发病机制中起着至关重要的作用。最后，昼夜节律机制调节 ER 应激相关途径，反之亦然，从而控制肝脏代谢的内稳态，并与 NAFLD 的进展有关。本文全面概述了支持 ER 应激信号对 NAFLD 影响的现有知识，同时总结了针对该过程的潜在治疗干预措施。
