Fibroblast growth factor 19 (FGF19) (FGF19)

Fibroblast growth factor 19 (FGF19) is an endocrine hormone primarily synthesized in ileal enterocytes in response to the activation of the farnesoid X receptor (FXR) by bile acids (Inagaki et al., 2005, Cell Metabolism). Once secreted, FGF19 travels through the portal circulation to the liver, where it binds to a receptor complex consisting of fibroblast growth factor receptor 4 (FGFR4) and the co-receptor beta-Klotho (Kurosu et al., 2007, JBC). This signaling pathway is a critical regulator of bile acid homeostasis, specifically by downregulating the expression of cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. Beyond bile acid regulation, FGF19 plays significant roles in glucose and lipid metabolism, making it a target of interest for metabolic diseases (Degirolamo et al., 2016, Nature Reviews Drug Discovery). Therapeutic strategies include the development of non-mitogenic FGF19 analogs, such as aldafermin, to treat conditions like metabolic dysfunction-associated steatohepatitis (MASH) and primary biliary cholangitis (PBC) without the oncogenic risks associated with wild-type FGF19 (Harrison et al., 2018, The Lancet). The pathway is also targeted indirectly by FXR agonists, which induce endogenous FGF19 production to manage cholestatic liver diseases and metabolic disorders. However, the mitogenic potential of wild-type FGF19 remains a significant safety concern, necessitating the engineering of analogs that decouple metabolic benefits from proliferative signaling.

Other names

FGF-19Fibroblast growth factor 19Ileal FGF19FGF19 pathway

FGF19 analogs or FXR-induced endogenous FGF19 activate the FGFR4/beta-Klotho receptor complex in hepatocytes, which triggers a signaling cascade that suppresses the expression of CYP7A1, thereby inhibiting the rate-limiting step of bile acid synthesis.