Department of Pediatrics, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000 Guizhou, China.
Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563000 Guizhou, China.
Biomed Res Int. 2021 Nov 5;2021:8717565. doi: 10.1155/2021/8717565. eCollection 2021.
Activating transcription factor 6 (ATF6) and receptor-interacting protein 3 (RIP3) are important signaling proteins in endoplasmic reticulum (ER) stress and necroptosis, respectively. However, their regulatory relationship and clinical significance are unknown. We investigate the impact of ATF6 on RIP3 expression, and its role in hepatocyte necroptosis in an acute liver injury model.
and experiments were carried out. LO2 cells were treated with thapsigargin (TG). , male BALB/c mice were treated with carbon tetrachloride (CCl, 1 mL/kg) or tunicamycin (TM, 2 mg/kg). Then, the impact of ATF6 or RIP3 silencing on liver injury, hepatocyte necroptosis, and ER stress-related protein expression was examined.
TG induced ER stress and necroptosis and ATF6 and RIP3 expression in LO2 cells. The knockdown of ATF6 significantly decreased RIP3 expression ( < 0.05) and increased ER stress and necroptosis. The downregulation of RIP3 significantly reduced necroptosis and ER stress ( < 0.05). Similar results were observed in CCl or the TM-induced mouse model. The knockdown of ATF6 significantly decreased CCl-induced RIP3 expression and increased liver injury, necroptosis, and ER stress in mice livers ( < 0.05). In contrast, the downregulation of RIP3 significantly reduced liver injury, hepatocyte necroptosis, and ER stress.
Hepatocyte ATF6 has multiple roles in acute liver injury. It reduces hepatocyte necroptosis via negative feedback regulation of ER stress. In addition, ATF6 can upregulate the expression of RIP3, which is not helpful to the recovery process. However, downregulating RIP3 reduces hepatocyte necroptosis by promoting the alleviation of ER stress. The findings suggest that RIP3 could be a plausible target for the treatment of liver injury.
激活转录因子 6（ATF6）和受体相互作用蛋白 3（RIP3）分别是内质网（ER）应激和坏死性凋亡的重要信号蛋白。然而，它们的调控关系及其临床意义尚不清楚。本研究旨在探讨 ATF6 对 RIP3 表达的影响及其在急性肝损伤模型中对肝细胞坏死性凋亡的作用。
进行了 和 实验。用他普西醇（TG）处理 LO2 细胞。雄性 BALB/c 小鼠用四氯化碳（CCl，1 mL/kg）或衣霉素（TM，2 mg/kg）处理。然后，观察 ATF6 或 RIP3 沉默对肝损伤、肝细胞坏死性凋亡和 ER 应激相关蛋白表达的影响。
TG 诱导 LO2 细胞发生 ER 应激和坏死性凋亡，并上调 ATF6 和 RIP3 的表达。ATF6 沉默显著降低 RIP3 表达（<0.05），增加 ER 应激和坏死性凋亡。RIP3 沉默显著减少坏死性凋亡和 ER 应激（<0.05）。在 CCl 或 TM 诱导的小鼠模型中也观察到类似结果。ATF6 沉默显著降低 CCl 诱导的 RIP3 表达，并增加小鼠肝脏的肝损伤、坏死性凋亡和 ER 应激（<0.05）。相反，RIP3 下调显著减轻肝损伤、肝细胞坏死性凋亡和 ER 应激。
肝细胞 ATF6 在急性肝损伤中具有多种作用。它通过负反馈调节 ER 应激减少肝细胞坏死性凋亡。此外，ATF6 可上调 RIP3 的表达，这对恢复过程无帮助。然而，下调 RIP3 通过促进 ER 应激的缓解减少肝细胞坏死性凋亡。这些发现表明 RIP3 可能是治疗肝损伤的一个合理靶点。
