Prometheus’ little helper, a novel role for fibroblast growth factor 15 in compensatory liver growth

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. Design: Liver regen- eration after PH was studied in Fgf15 � /� and Fgf15 +/+ mice. The effects of the BA sequestrant cholestyramine and adenovirally deliv- ered 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 accompa- nied by persistently elevated intrahepatic BA levels. Cholestyramine feeding and adenovirally delivered Fgf15 reduced BA levels and sig- nificantly prevented this lethal outcome. Fgf15 also reduced mortal- ity 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 signal- ing and proliferation of cultured hepatocytes and cholangiocytes. Conclusions: Fgf15 is necessary to maintain BA homeostasis and pre- vent 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 undergo- ing liver resection might be useful to reduce damage and foster regeneration. 2013 European Association for the Study of the Liver. Published