PMID- 37981257 OWN - NLM STAT- MEDLINE DCOM- 20231216 LR - 20231216 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 961 DP - 2023 Dec 15 TI - Glycyrrhetinic acid attenuates endoplasmic reticulum stress-induced hepatocyte apoptosis via CHOP/DR5/Caspase 8 pathway in cholestasis. PG - 176193 LID - S0014-2999(23)00707-0 [pii] LID - 10.1016/j.ejphar.2023.176193 [doi] AB - 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-alpha). 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-alpha. 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. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Zou, Bin AU - Zou B AD - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. FAU - Zhang, Shuang AU - Zhang S AD - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. FAU - Zhao, Jing AU - Zhao J AD - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. FAU - Song, Guochao AU - Song G AD - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. FAU - Weng, Fengyi AU - Weng F AD - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. FAU - Xu, Xiaoqing AU - Xu X AD - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. FAU - Li, Fengling AU - Li F AD - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. FAU - Jin, Jingyi AU - Jin J AD - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. FAU - Yan, Dongming AU - Yan D AD - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. FAU - Huang, Kai AU - Huang K AD - Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. FAU - Liu, Chenghai AU - Liu C AD - Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. Electronic address: chenghailiu@hotmail.com. FAU - Li, Yue AU - Li Y AD - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. Electronic address: yue_li1990@163.com. FAU - Qiu, Furong AU - Qiu F AD - Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201213, China. Electronic address: furong_qiu@126.com. LA - eng PT - Journal Article DEP - 20231120 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - P540XA09DR (Glycyrrhetinic Acid) RN - EC 3.4.22.- (Caspase 8) RN - 147336-12-7 (Transcription Factor CHOP) RN - EC 3.4.22.- (Caspases) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Mice MH - Animals MH - *Glycyrrhetinic Acid/pharmacology/therapeutic use MH - Caspase 8/metabolism MH - Mice, Inbred C57BL MH - *Cholestasis/metabolism MH - Apoptosis MH - Endoplasmic Reticulum Stress MH - Hepatocytes/metabolism MH - Transcription Factor CHOP/metabolism MH - Caspases/metabolism MH - Tumor Necrosis Factor-alpha/metabolism OTO - NOTNLM OT - Apoptosis OT - CCAAT/Enhancer-binding protein homologous protein OT - Cholestasis OT - Endoplasmic reticulum stress OT - Glycyrrhetinic acid COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/11/20 00:43 MHDA- 2023/12/17 09:42 CRDT- 2023/11/19 19:33 PHST- 2023/08/17 00:00 [received] PHST- 2023/10/19 00:00 [revised] PHST- 2023/11/07 00:00 [accepted] PHST- 2023/12/17 09:42 [medline] PHST- 2023/11/20 00:43 [pubmed] PHST- 2023/11/19 19:33 [entrez] AID - S0014-2999(23)00707-0 [pii] AID - 10.1016/j.ejphar.2023.176193 [doi] PST - ppublish SO - Eur J Pharmacol. 2023 Dec 15;961:176193. doi: 10.1016/j.ejphar.2023.176193. Epub 2023 Nov 20.