Figure 1.

Endocrine actions of FGF15. FGF15 expression is induced in the small intestine by bile acids acting on the FXR/RXR heterodimer. Secreted FGF15 acts on FGFR/β-Klotho receptor complexes in the liver to repress CYP7A1 and bile acid synthesis through a mechanism that requires SHP, to induce protein synthesis through activation of the ERK1/2–RSK pathway that activates translation factors S6 and eIF4B, to stimulate glycogen synthase (GS) activity and glycogen synthesis through inactivation of glycogen synthase kinase 3 (GSK3), and to repress gluconeogenesis by blocking the phosphorylation and activation of CREB, a transcription factor that induces peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and other gluconeogenic genes. FGF15 also acts on the gallbladder to increase cAMP levels, which promotes filling of the gallbladder with bile.