Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway
文献类型：期刊论文
| 作者 | Zhang, Tianwei2,3; Feng, Shanshan4; Li, Jiahuan4; Wu, Zhitao1,2; Deng, Qiangqiang2; Yang, Wei5; Li, Jing4 ; Pan, Guoyu2,3
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| 刊名 | ARCHIVES OF TOXICOLOGY
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| 出版日期 | 2022-03-10 |
| 页码 | 15 |
| 关键词 | FXR agonist Hepatotoxicity Farnesoid X receptor Obeticholic acid Px-102 Apoptosis |
| ISSN号 | 0340-5761 |
| DOI | 10.1007/s00204-022-03266-6 |
| 通讯作者 | Li, Jing(LiJing@hec.cn) ; Pan, Guoyu(gypan@simm.ac.cn) |
| 英文摘要 | Farnesoid X receptor (FXR) plays an indispensable role in liver homeostasis and has been a promising drug target for hepatic diseases. However, the concerns of undesired biological actions limit the clinical applications of FXR agonists. To reveal the intrinsic mechanism of FXR agonist-induce hepatotoxicity, two typical FXR agonists with different structures (obeticholic acid (OCA) and Px-102) were investigated in the present study. By detecting MMP, ROS, and ATP and analyzing the fate of cells, we found that both OCA and Px-102 reduced the mitochondrial function of hepatocytes and promoted cell apoptosis. Gene ablation or inhibition of FXR or SHP ameliorated the cytotoxicities of OCA and Px-102, which indicated the adverse actions of FXR/SHP activation including down-regulation of phosphorylation of PI3K/AKT and functional hepatic genes. The dose-related injurious effects of OCA (10 mg/kg and 30 mg/kg) and Px-102 (5 mg/kg and 15 mg/kg) on the liver were confirmed on a high-fat diet mouse model. The decrease of hepatocyte-specific genes and augmenter of liver regeneration in the liver caused by OCA or Px-102 suggested an imbalance of liver regeneration and a disruption of hepatic functions. Exploration of intestinally biased FXR agonists or combination of FXR agonist with apoptosis inhibitor may be more beneficial strategies for liver diseases. |
| WOS关键词 | OBETICHOLIC ACID ; SIGNALING PATHWAY ; DIFFERENTIATION ; REGULATOR ; CIRRHOSIS ; NASH ; MICE |
| 资助项目 | National Science Foundation of China[81872927] ; Organ Reconstruction and Manufacturing' Strategic Priority Research Program of the Chinese Academy of Sciences[XDA16020205] ; International Partnership Program of Chinese Academy of Sciences[153631KYSB20160004] ; Independent Deployment Program of the Institute of Pharmaceutical Innovation of the Chinese Academy of Sciences[CASIMM0120184005] ; Key Research and Development Program of Guangdong Province, China[2019B02021002] |
| WOS研究方向 | Toxicology |
| 语种 | 英语 |
| WOS记录号 | WOS:000767008400003 |
| 出版者 | SPRINGER HEIDELBERG |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/300218]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Li, Jing; Pan, Guoyu |
| 作者单位 | 1.Nanjing Univ Chinese Med, Nanjing 210029, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Sunshine Lake Pharma Co Ltd, Dept Pharmacol & Toxicol, Dongguan 523871, Peoples R China 5.Guangdong Lewwin Pharmaceut Res Inst Co Ltd, Guangdong Prov Key Lab Drug Nonclin Evaluat & Res, Guangzhou 510990, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Tianwei,Feng, Shanshan,Li, Jiahuan,et al. Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway[J]. ARCHIVES OF TOXICOLOGY,2022:15. |
| APA | Zhang, Tianwei.,Feng, Shanshan.,Li, Jiahuan.,Wu, Zhitao.,Deng, Qiangqiang.,...&Pan, Guoyu.(2022).Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway.ARCHIVES OF TOXICOLOGY,15. |
| MLA | Zhang, Tianwei,et al."Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway".ARCHIVES OF TOXICOLOGY (2022):15. |
入库方式： OAI收割
来源：上海药物研究所
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