title: Insufficient bile acid signaling impairs liver repair in CYP27(-/-) mice.
abstract: OBJECTIVE
  Previous studies indicate that bile acids (BAs) promote normal liver regeneration and repair after injury. However, the impact of insufficient BA signaling, which is observed in patients with BA sequestrant medication or cerebrotendinous xanthomatosis (CTX) disease, on liver injury is still unknown. Our aim is to determine the outcomes of reduced BA levels upon liver injury.
  
  
  METHODS
  Seventy percent partial hepatectomy (PH) and carbon tetrachloride (CCl(4)) treatment were performed using CYP27(-/-) mice, a genetic animal model with low BA levels. The liver repair of CYP27(-/-) mice after the treatments was characterized by histological staining, chemical analysis, and quantitative real-time PCR.
  
  
  RESULTS
  CYP27(-/-) mice exhibited enhanced CCl(4)-induce liver injury, and defective liver regeneration and prolonged steatosis after 70% PH. Due to the insufficient BA signaling, farnesoid X receptor (FXR) activities were significantly reduced in CYP27(-/-) livers after 70% PH. Activation of FXR by either 0.2% cholic acid feeding or oral infusion of an FXR agonist greatly promoted liver regeneration in CYP27(-/-) mice.
  
  
  CONCLUSIONS
  Normal physiological levels of BAs are required for liver repair. Patients with BA sequestrant medications or CTX disease due to CYP27 gene mutations may have an increased risk of liver failure, and treatment with FXR ligands can promote liver regeneration of patients with low BA levels.
authors.affiliation: Division of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Meng
authors.forename: Nian
authors.initials: N
authors.lastname: Liu
authors.forename: Xianghui
authors.initials: X
authors.lastname: Fu
authors.forename: Xiaoqiong
authors.initials: X
authors.lastname: Wang
authors.forename: Yan-Dong
authors.initials: YD
authors.lastname: Wang
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Chen
authors.forename: Lisheng
authors.initials: L
authors.lastname: Zhang
authors.forename: Barry M
authors.initials: BM
authors.lastname: Forman
authors.forename: Wendong
authors.initials: W
authors.lastname: Huang
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D002251:Carbon Tetrachloride / Q000633:toxicity; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006498:Hepatectomy / Q000379:methods; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019294:Xanthomatosis, Cerebrotendinous / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002251:Carbon Tetrachloride; D053493:Cholestanetriol 26-Monooxygenase; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C491524:Foxm1 protein, mouse