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
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.
DESIGN: 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.
Uriarte I et al. Gut. 2013 Jun;62(6):899-910