We have read with interest Dr Mats Rudling's letter regarding our recent article on the role of Fgf15 in liver regeneration and the liver growth-promoting effects of bile acids.1 Our work was based on the use of Fgf15 knockout mice, and in these mice we indeed found impaired liver regeneration and bile acid metabolism after partial hepatectomy and reduced liver cell proliferation upon bile acid feeding.2 The fact that FGFR4 deficient mice do not show alterations in liver regeneration after partial hepatectomy described by Yu et al 3 suggests the existence of compensatory mechanisms in mice lacking this receptor, as discussed by the authors of that study. The nature of these compensatory mechanisms is presently unknown. However FGF19 has been shown to trigger promitogenic mitogen-activated protein kinase signalling also through FGFR2 and FGFR3 variants, some of which can be found in liver tissue.4 Moreover, albeit to a lesser extent than in wild type mice, FGF19 administration to FGFR4 knockout mice still induces the expression of proliferation-related genes (Egr-1) and reduces that of Cyp7a1.5 Therefore the existence of FGFR4-independent effects of Fgf15 in the context of liver regeneration and bile acid synthesis is possible and merits further investigations.

Certainly Fgf15 protein has not been detected so far in rodent plasma, but as mentioned by the author, enterohepatic circulation of Fgf15 is the most prevalent working model for the action of this growth factor; see for instance the work of Sayin et al 6 and references therein. The existence of alternative mechanisms for Fgf15-caused effects on bile acid synthesis is a very interesting possibility that will attract much attention. In any case, our data showed that in the absence of Fgf15 the regulation of bile acid levels during mouse liver regeneration was impaired.

Finally, the concentrations of FGF19 used in our in vitro experiments, including cell proliferation studies, were consistent with those previously used on human and rodent liver cells, making our observations comparable with those in the current literature; see for instance Kir et al.7 Nevertheless, we also demonstrated that in vivo delivery of Fgf15 elicited clear hepatoprotective and proregenerative responses in mice.2