Glycosylation of fibroblast growth factor receptor 4 is a key regulator of fibroblast growth factor 19–mediated down‐regulation of cytochrome P450 7A1†

UNLABELLED: De novo bile acid synthesis in the liver needs to be tightly regulated in order to maintain optimal bile flow and prevent cholestasis. In the liver, fibroblast growth factor 19 (FGF19) regulates bile acid synthesis by down-regulating messenger RNA levels of cytochrome P450 7A1 (CYP7A1). FGF19 acts through fibroblast growth factor receptor 4 (FGFR4), and beta-Klotho has recently been recognized as a modulator of FGFR4 activity. However, its precise mechanism of action has not been thoroughly described. We show here that beta-Klotho is an endoplasmic reticulum-resident protein that affects the cellular abundance of different FGFR4 glycoforms. beta-Klotho binds and directs the core glycoform of FGFR4 to the proteasome, and it allows only a terminal glycoform to reach the plasma membrane. Only the terminal FGFR4 glycoform is phosphorylated upon FGF19 treatment of HepG2 cells, and this shows that only fully glycosylated FGFR4 is active in CYP7A1 down-regulation. CONCLUSION: beta-Klotho enhances FGF19 signaling by binding the inactive, core-glycosylated FGFR4 and preventing it from reaching the surface. These results indicate that beta-Klotho is an indirect regulator of FGFR4, whereas glycosylation is the master switch for FGF19 activity and regulation of bile acid synthesis.