Bile acid (BA)-induced apoptosis is a common pathologic feature of cholestatic liver injury. Glycyrrhetinic acid (GA) is the hepatoprotective constituent of licorice. In the present study, the anti-apoptotic potential of GA was investigated in wild type and macrophage-depleted C57BL/6 mice challenged with alpha-naphthyl isothiocyanate (ANIT), and hepatocytes stimulated with Taurocholic acid (TCA) or Tumor necrosis factor-alpha (TNF-α). Apoptosis was determined by TUNEL positive cells and expression of executioner caspases. Firstly, we found that GA markedly alleviated liver injury, accompanied with reduced positive TUNEL-staining cells, and expression of caspases 3, 8 and 9 in mice modeled with ANIT. Secondly, GA mitigated apoptosis in macrophage-depleted mice with exacerbated liver injury and augmented cell apoptosis. In vitro study, pre-treatment with GA reduced the expression of activated caspases 3 and 8 in hepatocytes stimulated with TCA, but not TNF-α. The ability of GA to ameliorate apoptosis was abolished in the presence of Tauroursodeoxycholic Acid (TUDCA), a chemical chaperon against Endoplasmic reticulum stress (ER stress). Furthermore, GA attenuated the over-expression of Glucose regulated protein 78 (GRP78), and blocked all three branches of Unfolded protein reaction (UPR) in cholestatic livers of mice induced by ANIT. GA also downregulated C/EBP homologous protein (CHOP) expression, accompanied with reduced expression of Death receptor 5 (DR5) and activation of caspase 8 in both ANIT-modeled mice and TCA-stimulated hepatocytes. The results indicate that GA inhibits ER stress-induced hepatocyte apoptosis in cholestasis, which correlates with blocking CHOP/DR5/Caspase 8 pathway.

胆汁酸（BA）诱导的细胞凋亡是胆汁淤积性肝损伤的常见病理特征。甘草次酸 (GA) 是甘草的保肝成分。在本研究中，在用α-萘基异硫氰酸酯（ANIT）攻击的野生型和巨噬细胞耗尽的C57BL/6小鼠以及用牛磺胆酸（TCA）或肿瘤坏死因子-α刺激的肝细胞中研究了GA的抗凋亡潜力。 （肿瘤坏死因子-α）。通过 TUNEL 阳性细胞和刽子手半胱天冬酶的表达来测定细胞凋亡。首先，我们发现 GA 显着减轻了 ANIT 模型小鼠的肝损伤，同时 TUNEL 染色阳性细胞以及 caspase 3、8 和 9 的表达减少。其次，GA 可以减轻巨噬细胞耗尽小鼠的细胞凋亡，从而加剧肝损伤并增加细胞凋亡。体外研究中，GA 预处理可降低 TCA 刺激的肝细胞中活化的 caspase 3 和 8 的表达，但不会降低 TNF-α 刺激的肝细胞。牛磺熊去氧胆酸 (TUDCA) 是一种对抗内质网应激 (ER 应激) 的化学伴侣，GA 改善细胞凋亡的能力被消除。此外，GA 减弱了葡萄糖调节蛋白 78 (GRP78) 的过度表达，并阻断了 ANIT 诱导的小鼠胆汁淤积性肝脏中未折叠蛋白反应 (UPR) 的所有三个分支。 GA 还下调了 ANIT 模型小鼠和 TCA 刺激的肝细胞中 C/EBP 同源蛋白 (CHOP) 的表达，并伴有死亡受体 5 (DR5) 表达的减少和 caspase 8 的激活。结果表明，GA 抑制胆汁淤积时 ER 应激诱导的肝细胞凋亡，这与阻断 CHOP/DR5/Caspase 8 通路相关。