The ileal FGF15/19 to hepatic FGFR4 axis regulates liver regeneration after partial hepatectomy in mice

Fibroblast growth factor (FGF) has been considered to modulate liver regeneration (LR) after partial hepatectomy (PH) at the tissue level. Previous studies have demonstrated that FGF15 and FGF19 induce the activation of its receptor, FGF receptor 4 (FGFR4), which can promote hepatocellular carcinoma progression and regulate liver lipid metabolism. In this study, we aimed to explore the role of the ileal FGF15/19- hepatic FGFR4 axis in the LR after PH. Male C57BL/6 mice aged 8-12 weeks were partially hepatectomized and assessed for expression of ileal FGF15/19 to hepatic FGFR4 signaling. We used recombinant human FGF19 protein and a small interfering RNA (siRNA) of FGFR4 to regulate expression of the FGF15/19-FGFR4 axis in vitro and in vivo. The proliferation and cell cycle of hepatocytes, the expression levels of FGF15/19-FGFR4 downstream molecules, liver recovery, and lipid metabolism were assessed. We found that both ileal and serum FGF15 expression were upregulated and hepatic FGFR4 was activated after PH in mice. FGF15/19 promoted cell cycle progression, enhanced proliferation, and reduced hepatic lipid accumulation of hepatocytes both in vitro and in vivo. Furthermore, the proliferative effect and lipid regulatory properties of FGF15/19 were dependent on FGFR4 in hepatocytes. In addition, ileal FGF15/19-hepatic FGFR4 transduction during hepatocyte proliferation was regulated by extracellular regulated protein kinase (ERK) 1/2. In conclusion, the ileal FGF15/19 to hepatic FGFR4 axis is activated and promotes LR after PH in mice, supporting the potential of ileal FGF15/19 to hepatic FGFR4 axis-targeted therapy to enhance LR after PH.