Fibroblast growth factor 19 (FGF19) plays a crucial role in the negative feedback regulation of bile salt synthesis. In the postprandial state, activation of ileal farnesoid X receptor (FXR) by bile salts results in transcriptional induction of FGF19 and elevation of circulating FGF19 levels. An intestinal-liver axis of FGF19 signaling results in down-regulation of bile salt synthesis. The aim of this study was to explore a broader signaling activity of FGF19 in organs engaged in the enterohepatic circulation of bile salts. For this aim, FGF19 expression and aspects of FGF19 signaling were studied in surgical specimens and in cell lines of hepatobiliary and intestinal origin. FGF19 messenger RNA was found to be abundantly expressed in the human gallbladder and in the common bile duct, with only minor expression observed in the ileum. Interestingly, human gallbladder bile contains high levels of FGF19 (21.9 +/- 13.3 versus 0.22 +/- 0.14 ng/mL in the systemic circulation). Gallbladder explants secrete 500 times more FGF19 than FXR agonist-stimulated ileal explants. Factors required for FGF19 signaling (i.e., FGFR4 and betaKlotho) are expressed in mucosal epithelial cells of the gallbladder and small intestine. FGF19 was found to activate signaling pathways in cell lines of cholangiocytic, enteroendocrine, and enterocytic origin. CONCLUSION: The combined findings raise the intriguing possibility that biliary FGF19 has a signaling function in the biliary tract that differs from its established signaling function in the portal circulation. Delineation of the target cells in bile-exposed tissues and the affected cellular pathways, as well as a possible involvement in biliary tract disorders, require further studies.