Insufficient bile acid signaling impairs liver repair in CYP27(-/-) mice

J Hepatol. 2011 Oct;55(4):885-95. doi: 10.1016/j.jhep.2010.12.037. Epub 2011 Feb 18.


Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / blood
  • Bile Acids and Salts / metabolism*
  • Carbon Tetrachloride / toxicity
  • Cell Proliferation
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / physiopathology*
  • Cholestanetriol 26-Monooxygenase / genetics
  • Cholestanetriol 26-Monooxygenase / metabolism*
  • Disease Models, Animal
  • Fatty Liver / genetics
  • Fatty Liver / metabolism
  • Fatty Liver / physiopathology
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / metabolism
  • Hepatectomy / methods
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Liver Regeneration / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Signal Transduction / physiology*
  • Xanthomatosis, Cerebrotendinous / genetics
  • Xanthomatosis, Cerebrotendinous / metabolism
  • Xanthomatosis, Cerebrotendinous / physiopathology


  • Bile Acids and Salts
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Foxm1 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • farnesoid X-activated receptor
  • Carbon Tetrachloride
  • Cholestanetriol 26-Monooxygenase