College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea; College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeongsangbuk-do 38610, Republic of Korea.
Toxicol Appl Pharmacol. 2020 Jul 15;399:115036. doi: 10.1016/j.taap.2020.115036. Epub 2020 May 11.
Endoplasmic reticulum (ER) stress designates a cellular response to the accumulation of misfolded proteins, which is related to disease progression in the liver. Luteolin (3',4',5,7-tetrahydroxyflavone) is a phytochemical found frequently in medicinal herbs. Although luteolin has been reported to possess the therapeutic potential to prevent diverse stage of liver diseases, its role in hepatic ER stress has not been established. Thus, the present study aimed to determine the role of luteolin in tunicamycin (Tm)-induced ER stress, and to identify the relevant mechanisms involved in its hepatoprotective effects. In hepatocyte-derived cells and primary hepatocytes, luteolin significantly decreased Tm- or thapsigargin-mediated C/EBP homologous protein (CHOP) expression. In addition, luteolin reduced the activation of three canonical signaling pathways related to the unfolded protein response, and decreased mRNA levels of glucose-regulated protein 78, ER DNA J domain-containing protein 4, and asparagine synthetase. Luteolin also significantly upregulated sestrin 2 (SESN2), and luteolin-mediated CHOP inhibition was blocked in SESN2 (+/-) cells. Moreover, luteolin resulted in phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), as well as increased nuclear Nrf2 expression. Deletion of the antioxidant response element in the human SESN2 promoter inhibited increased luciferase activation by luteolin, suggesting that Nrf2 is a critical transcription factor for luteolin-dependent SESN2 expression. In a Tm-mediated liver injury model, luteolin decreased serum alanine aminotransferase and aspartate aminotransferase activities, prevented degenerative changes and apoptosis of hepatocytes, and inhibited CHOP and glucose-regulated protein 78 expression in hepatic tissues. Therefore, luteolin may be an effective phytochemical to manage ER stress-related liver injury.
内质网（ER）应激是指细胞对错误折叠蛋白积累的反应，与肝脏疾病的进展有关。木樨草素（3'，4'，5，7-四羟基黄酮）是一种经常在草药中发现的植物化学物质。尽管已经报道木樨草素有预防多种阶段的肝病的治疗潜力，但它在肝 ER 应激中的作用尚未确定。因此，本研究旨在确定木樨草素在衣霉素（Tm）诱导的 ER 应激中的作用，并确定其肝保护作用涉及的相关机制。在肝细胞来源的细胞和原代肝细胞中，木樨草素显著降低了 Tm 或他普西坦介导的 C/EBP 同源蛋白（CHOP）表达。此外，木樨草素降低了与未折叠蛋白反应相关的三个经典信号通路的激活，并降低了葡萄糖调节蛋白 78、ER DNA J 结构域蛋白 4 和天冬酰胺合成酶的 mRNA 水平。木樨草素还显著上调了 sestrin 2（SESN2），并且在 SESN2（+/-）细胞中阻断了木樨草素介导的 CHOP 抑制。此外，木樨草素导致核因子红细胞 2 相关因子 2（Nrf2）的磷酸化，并增加了核 Nrf2 表达。人 SESN2 启动子中抗氧化反应元件的缺失抑制了木樨草素增加的荧光素酶激活，表明 Nrf2 是木樨草素依赖的 SESN2 表达的关键转录因子。在 Tm 介导的肝损伤模型中，木樨草素降低了血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶活性，防止了肝细胞的退行性变化和凋亡，并抑制了肝组织中 CHOP 和葡萄糖调节蛋白 78 的表达。因此，木樨草素可能是一种有效的管理与内质网应激相关的肝损伤的植物化学物质。
