Glycyrrhetinic acid attenuates endoplasmic reticulum stress-induced hepatocyte apoptosis via CHOP/DR5/Caspase 8 pathway in cholestasis

  • Eur J Pharmacol. 2023 Nov 20:961:176193. doi: 10.1016/j.ejphar.2023.176193.
Bin Zou  1 ,  Shuang Zhang  1 ,  Jing Zhao  1 ,  Guochao Song  1 ,  Fengyi Weng  1 ,  Xiaoqing Xu  1 ,  Fengling Li  1 ,  Jingyi Jin  1 ,  Dongming Yan  1 ,  Kai Huang  2 ,  Chenghai Liu  3 ,  Yue Li  4 ,  Furong Qiu  5
Affiliations
  • 1. Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China.
  • 2. Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China.
  • 3. Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. Electronic address: [email protected].
  • 4. Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. Electronic address: [email protected].
  • 5. Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. Electronic address: [email protected].
PMID: 37981257 DOI: 10.1016/j.ejphar.2023.176193
Abstract

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.

Keywords
Apoptosis; CCAAT/Enhancer-binding protein homologous protein; Cholestasis; Endoplasmic reticulum stress; Glycyrrhetinic acid.
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