title: Activation of the farnesoid X receptor attenuates triptolide-induced liver toxicity.
abstract: BACKGROUND
  Triptolide, an active ingredient extracted from the Chinese herb Tripterygium wilfordii Hook f., has multiple pharmacological properties, including anti-inflammatory, immune-modulatory, and anti-proliferative activities. However, the hepatotoxicity of triptolide always limits its clinical applications.
  
  
  OBJECTIVE
  Farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays a key role in hepatoprotection through the maintenance of liver metabolism homeostasis. This study explored the role of FXR in triptolide-induced cytotoxicity and investigated whether activation of FXR can protect against triptolide-induced liver injury.
  
  
  METHODS
  The role of FXR in triptolide-induced cytotoxicity was investigated in HepG2 cells. In addition, the protective effect of the selective FXR agonist GW4064 on triptolide-induced hepatotoxicity was explored in BALB/c mice.
  
  
  METHODS
  HepG2 cells were transient transfected with FXR expression plasmid or FXR-siRNA. The cytotoxicity was compared using the MTT assay. The extent of liver injury was assessed by histopathology and serum aminotransferases. The expression of FXR and its target genes were detected by Western blot and qRT-PCR.
  
  
  RESULTS
  The transient overexpression of FXR protected against triptolide-induced cell death, whereas FXR knockdown with a specific small interfering RNA resulted in increased cytotoxicity. In BALB/c mice, treatment with the FXR agonist GW4064 attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and lipid peroxidation. Moreover, the livers of GW4064-treated mice showed increased expression of FXR and several related target genes involved in phase II and phase III xenobiotic metabolism.
  
  
  CONCLUSIONS
  Taken together, these results indicate that activation of FXR attenuates triptolide-induced hepatotoxicity and provide direct implications for the development of novel therapeutic strategies against triptolide-induced hepatotoxicity.
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors: Jing
authors: J
authors: Jin
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors: Xiaozhe
authors: X
authors: Sun
authors: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, PR China.
authors: Zhongxiang
authors: Z
authors: Zhao
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors: Wenwen
authors: W
authors: Wang
authors: Center of Laboratory animals, Sun Yat-sen University, Guangzhou 510006, PR China.
authors: Yuwen
authors: Y
authors: Qiu
authors: Center of Laboratory animals, Sun Yat-sen University, Guangzhou 510006, PR China.
authors: Xinlu
authors: X
authors: Fu
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
authors: Min
authors: M
authors: Huang
authors: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Center of Laboratory animals, Sun Yat-sen University, Guangzhou 510006, PR China. Electronic address: hzhiying@mail.sysu.edu.cn.
authors: Zhiying
authors: Z
authors: Huang
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D004224:Diterpenes / Q000633:toxicity*; D004852:Epoxy Compounds / Q000633:toxicity; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D008099:Liver / Q000187:drug effects*; D008297:Male; D008807:Mice, Inbred BALB C; D010616:Phenanthrenes / Q000633:toxicity*; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D004224:Diterpenes; D004852:Epoxy Compounds; D007555:Isoxazoles; D010616:Phenanthrenes; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C001899:triptolide; C412815:GW 4064
keywords: FXR; GW4064; Hepatotoxicity; Mice; Triptolide