FGFR4KLB

FGFR4KLB refers to the functional receptor complex formed by fibroblast growth factor receptor 4 (FGFR4) and the co-receptor beta-klotho (KLB). This complex mediates signaling of the endocrine fibroblast growth factors, most notably FGF19, enabling receptor activation in tissues such as the liver. The FGFR4-KLB assembly provides tissue specificity for FGF19 and related ligands, and is distinct from signaling by other FGFR–KLB combinations in adipose or other tissues.

Mechanistically, binding of FGF19 to the FGFR4–KLB complex promotes receptor dimerization and tyrosine kinase–driven signaling. Activated pathways typically include the MAPK/ERK cascade and associated downstream effectors, culminating in transcriptional changes. A principal physiological outcome is the suppression of hepatic bile acid synthesis, accomplished through downregulation of the CYP7A1 gene, helping to maintain bile acid homeostasis. FGFR4-KLB signaling also intersects with metabolic regulation and growth signaling, with broader implications for energy balance and liver function.

Tissue distribution and ligands: FGFR4 and KLB are enriched in the liver, where FGF19, produced in the ileum in response to FXR activation, serves as a circulating ligand. While FGF21 signals through different FGFRs and co-receptors in other tissues, FGFR4–KLB is the principal hepatic receptor complex for FGF19.

Clinical significance: Dysregulation of the FGFR4–KLB axis can affect bile acid homeostasis and contribute to liver diseases such as cholestasis and nonalcoholic fatty liver disease. Polymorphisms in FGFR4 and aberrant FGFR4 signaling have been studied for cancer prognosis. Therapeutically, targeting the FGFR4–KLB axis is of interest for cholestatic and metabolic diseases, and FGF19-based strategies (for example, FGF19 analogs like Aldafermin/NGM282) or FGFR4 inhibitors are in clinical development, with attention to balancing metabolic benefits against potential tumorigenic risks.