title: Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice.
abstract: OBJECTIVE
  Cholestasis is associated with increased liver injury and morbidity after partial hepatectomy (PH), yet bile acids (BAs) are emerging as important mediators of liver regeneration. Fibroblast growth factor 15 (Fgf15, human FGF19) is a BA-induced ileum-derived enterokine that governs BA metabolism. We evaluated the relevance of Fgf15 in the preservation of BA homeostasis after PH and its potential role in the regenerative process.
  
  
  METHODS
  Liver regeneration after PH was studied in Fgf15 (-/-) and Fgf15 (+/+) mice. The effects of the BA sequestrant cholestyramine and adenovirally delivered Fgf15 were examined in this model. The role of Fgf15 in BA-induced liver growth was tested in Fgf15 (-/-) mice upon cholic acid (CA) feeding. The direct mitogenic effect of Fgf15 was evaluated in cultured mouse hepatocytes and cholangiocytes.
  
  
  RESULTS
  Fgf15 (-/-) mice showed marked liver injury and mortality after PH accompanied by persistently elevated intrahepatic BA levels. Cholestyramine feeding and adenovirally delivered Fgf15 reduced BA levels and significantly prevented this lethal outcome. Fgf15 also reduced mortality after extensive hepatectomy in Fgf15(+/+) animals. Liver growth elicited by CA feeding was significantly diminished in Fgf15 (-/-) mice. Proliferation of hepatocytes and cholangiocytes was also noticeably reduced in CA-fed Fgf15 (-/-) mice. Fgf15 induced intracellular signalling and proliferation of cultured hepatocytes and cholangiocytes.
  
  
  CONCLUSIONS
  Fgf15 is necessary to maintain BA homeostasis and prevent liver injury during liver regeneration. Moreover, Fgf15 is an essential mediator of the liver growth-promoting effects of BA. Preoperative administration of this enterokine to patients undergoing liver resection might be useful to reduce damage and foster regeneration.
authors.affiliation: Division of Hepatology and Gene Therapy, CIMA, University of Navarra, Clinic University of Navarra and CIBERehd, Pamplona, Spain.
authors.forename: Iker
authors.initials: I
authors.lastname: Uriarte
authors.forename: Maite G
authors.initials: MG
authors.lastname: Fernandez-Barrena
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Monte
authors.forename: Maria U
authors.initials: MU
authors.lastname: Latasa
authors.forename: Haisul C Y
authors.initials: HC
authors.lastname: Chang
authors.forename: Simone
authors.initials: S
authors.lastname: Carotti
authors.forename: Umberto
authors.initials: U
authors.lastname: Vespasiani-Gentilucci
authors.forename: Sergio
authors.initials: S
authors.lastname: Morini
authors.forename: Eva
authors.initials: E
authors.lastname: Vicente
authors.forename: Axel R
authors.initials: AR
authors.lastname: Concepcion
authors.forename: Juan F
authors.initials: JF
authors.lastname: Medina
authors.forename: José Juan G
authors.initials: JJ
authors.lastname: Marin
authors.forename: Carmen
authors.initials: C
authors.lastname: Berasain
authors.forename: Jesus
authors.initials: J
authors.lastname: Prieto
authors.forename: Matías A
authors.initials: MA
authors.lastname: Avila
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000502:physiology*; D006498:Hepatectomy; D006706:Homeostasis / Q000502:physiology; D017093:Liver Failure / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control*; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011183:Postoperative Complications
chemical_list: D001647:Bile Acids and Salts; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors