2. Academic Validation
  3. Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway

Farnesoid X receptor (FXR) agonists induce hepatocellular apoptosis and impair hepatic functions via FXR/SHP pathway

  • Arch Toxicol. 2022 Jun;96(6):1829-1843. doi: 10.1007/s00204-022-03266-6.
Tianwei Zhang  # 1 2,  Shanshan Feng  # 3,  Jiahuan Li 3,  Zhitao Wu 1 4,  Qiangqiang Deng 1,  Wei Yang 5,  Jing Li 6,  Guoyu Pan 7 8
Affiliations

Affiliations

  • 1 Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Department of Pharmacology and Toxicology, Sunshine Lake Pharma Co., Ltd., Dongguan, 523871, China.
  • 4 Nanjing University of Chinese Medicine, Nanjing, 210029, China.
  • 5 Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and Research, Guangdong Lewwin Pharmaceutical Research Institute Co., Ltd., Guangzhou, 510990, China.
  • 6 Department of Pharmacology and Toxicology, Sunshine Lake Pharma Co., Ltd., Dongguan, 523871, China. LiJing@hec.cn.
  • 7 Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, 201203, China. gypan@simm.ac.cn.
  • 8 University of Chinese Academy of Sciences, Beijing, 100049, China. gypan@simm.ac.cn.
  • # Contributed equally.
PMID: 35267068 DOI: 10.1007/s00204-022-03266-6
Abstract

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.

Keywords

Apoptosis; FXR agonist; Farnesoid X receptor; Hepatotoxicity; Obeticholic acid; Px-102.

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