Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University, Uchinada-machi, Ishikawa, 920-0293, Japan.
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University, Kure, Hiroshima, 737-0112, Japan.
Sci Rep. 2017 Oct 27;7(1):14282. doi: 10.1038/s41598-017-14711-3.
Hepatocyte cell death is a key feature of nonalcoholic steatohepatitis (NASH); however, the pathogenesis of NASH currently remains unclear. We aimed to investigate the effects of intracellular glyceraldehyde (GA)-derived advanced glycation end-products (GA-AGEs) on human hepatocyte cell death. The accumulation of intracellular GA-AGEs has been associated with the induction of DNA damage and hepatocyte necrotic cell death. Among intracellular GA-AGEs, caspase-3 has been identified as a GA-AGE-modified protein with abrogated protein function. Furthermore, the activation of caspase-3 and induction of hepatocyte apoptosis by camptothecin, a DNA-damaging agent, was suppressed by a treatment with GA. These results suggest the inhibitory effects of GA-AGE-modified caspase-3 on the induction of DNA-damage-induced apoptosis, which is associated with hepatocyte necrosis. Therefore, the suppression of necrosis, the inflammatory form of cell death, by the accumulation of GA-AGEs and GA-AGE-modified caspase-3 may represent a novel therapeutic target for the pathogenesis of NASH.
肝细胞死亡是非酒精性脂肪性肝炎（NASH）的一个关键特征；然而，NASH 的发病机制目前仍不清楚。我们旨在研究细胞内甘油醛（GA）衍生的晚期糖基化终产物（GA-AGEs）对人肝细胞死亡的影响。细胞内 GA-AGEs 的积累与诱导 DNA 损伤和肝细胞坏死性细胞死亡有关。在细胞内 GA-AGEs 中，已鉴定出 caspase-3 是一种 GA-AGE 修饰蛋白，其蛋白功能被阻断。此外，用 GA 处理可抑制喜树碱（一种 DNA 损伤剂）诱导的 caspase-3 激活和肝细胞凋亡。这些结果表明，GA-AGE 修饰的 caspase-3 对诱导 DNA 损伤诱导的凋亡具有抑制作用，这与肝细胞坏死有关。因此，GA-AGE 和 GA-AGE 修饰的 caspase-3 的积累抑制坏死（细胞死亡的炎症形式）可能代表 NASH 发病机制的一个新的治疗靶点。
