Fibroblast growth factor receptor 1c-alpha-Klotho complex (FGFR1c-KL)

The Fibroblast growth factor receptor 1c (FGFR1c)-alpha-Klotho complex is a specialized heterodimeric receptor system required for the biological activity of endocrine fibroblast growth factors, primarily FGF21 and FGF23 (Nature, 2018, 553:501-505). Unlike paracrine FGFs that utilize heparan sulfate as a co-receptor, endocrine FGFs have a low affinity for heparin and must bind to the transmembrane protein alpha-Klotho, which acts as a scaffold to facilitate high-affinity binding to FGFR1c (UniProt P11362, Q9GZT9). This complex is a critical regulator of metabolic homeostasis; in adipose tissue, FGF21 signaling through FGFR1c-alpha-Klotho stimulates glucose uptake and thermogenesis, while in the liver, it modulates lipid metabolism and reduces fat accumulation (Cell Metabolism, 2014, 19:810-822). In the renal system, the complex mediates the phosphaturic effects of FGF23, maintaining mineral balance (Journal of Internal Medicine, 2012, 272:347-359). Pharmacological targeting of this complex with FGF21 mimetics like efruxifermin and pegozafermin is currently a major focus for treating metabolic dysfunction-associated steatohepatitis (MASH) and severe hypertriglyceridemia (The Lancet, 2023, 402:239-252). Potential safety concerns associated with modulating this pathway include impacts on bone mineral density and gastrointestinal tolerability (Expert Opinion on Investigational Drugs, 2020, 29:1231-1243).

Other names

FGFR1c-alpha-Klotho complexFGFR1c-KL complexFGF21 receptor complexFGF23 receptor complexFibroblast growth factor receptor 1 isoform c-alpha-Klotho

Agonism of the FGFR1c-alpha-Klotho complex to activate intracellular signaling pathways, such as MAPK/ERK and PI3K/Akt, which regulate systemic glucose and lipid metabolism.