Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku, Ishikawa 920-0293, Japan.
Int J Mol Sci. 2020 Jul 9;21(14):4861. doi: 10.3390/ijms21144861.
Hepatocyte cell death is a key process in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the factors responsible for and mechanisms underlying NASH-related cell death have not yet been elucidated in detail. We herein investigated the effects of intracellular glyceraldehyde (GA)-derived advanced glycation end-products (AGEs), named toxic AGEs (TAGE), on the production of reactive oxygen species (ROS), which have been implicated in the pathogenesis of NASH. Cell death related to intracellular TAGE accumulation was eliminated in the hepatocyte carcinoma cell line HepG2 by the antioxidant effects of N-acetyl-L-cysteine. The intracellular accumulation of TAGE increased ROS production and the expression of Nrf2, including its downstream gene. These results suggest that ROS are produced in association with the accumulation of TAGE and are a direct trigger for cell death. We also investigated the factors responsible for these increases in ROS. Catalase activity did not decrease with the accumulation of TAGE, while mitochondrial membrane depolarization was enhanced in cells treated with GA. These results indicate that TAGE play an important role in mitochondrial abnormalities and increases in ROS production, both of which are characteristic features of NASH. The suppression of TAGE accumulation has potential as a new therapeutic target in the progression of NASH.
肝细胞死亡是非酒精性脂肪性肝炎（NASH）发病机制中的关键过程。然而，导致 NASH 相关细胞死亡的因素和机制尚未详细阐明。在此，我们研究了细胞内甘油醛（GA）衍生的高级糖基化终产物（AGE），称为毒性 AGE（TAGE）对活性氧（ROS）产生的影响，ROS 被认为与 NASH 的发病机制有关。抗氧化剂 N-乙酰-L-半胱氨酸的作用消除了肝癌细胞系 HepG2 中与细胞内 TAGE 积累有关的细胞死亡。TAGE 的细胞内积累增加了 ROS 的产生和 Nrf2 的表达，包括其下游基因。这些结果表明，ROS 的产生与 TAGE 的积累有关，是细胞死亡的直接触发因素。我们还研究了导致这些 ROS 增加的因素。随着 TAGE 的积累，过氧化氢酶活性并没有降低，而用 GA 处理的细胞中线粒体膜去极化增强。这些结果表明，TAGE 在线粒体异常和 ROS 产生增加中起重要作用，这两者都是 NASH 的特征。抑制 TAGE 积累可能成为 NASH 进展的新治疗靶点。
