Journal of hepatology · 2011
Insufficient bile acid signaling impairs liver repair in CYP27(-/-) mice.
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Meng Zhipeng, Liu Nian, Fu Xianghui, Wang Xiaoqiong, Wang Yan-Dong, Chen Wei-Dong, Zhang Lisheng, Forman Barry M, Huang Wendong
Аннотация
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.
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.
Предметные рубрики MeSH
AnimalsBile Acids and SaltsCarbon TetrachlorideCell ProliferationChemical and Drug Induced Liver InjuryCholestanetriol 26-MonooxygenaseDisease Models, AnimalFatty LiverForkhead Box Protein M1Forkhead Transcription FactorsHepatectomyHepatocytesLiver RegenerationMiceMice, Inbred C57BLMice, Mutant StrainsReceptors, Cytoplasmic and NuclearSignal TransductionXanthomatosis, CerebrotendinousReceptor, Farnesoid X-Activated