Fibroblast growth factor receptor 1c-Klotho beta receptor complex (FGFR1c-KLB)

The Fibroblast growth factor receptor 1c-Klotho beta (FGFR1c-KLB) receptor complex is a specialized heteromeric signaling assembly essential for the activity of the metabolic hormone Fibroblast Growth Factor 21 (FGF21) (UniProt P11362, Q86Z14). While FGFR1c is a widely distributed receptor tyrosine kinase, its high-affinity interaction with FGF21 is strictly dependent on the presence of the transmembrane protein Klotho beta (KLB), which acts as an essential co-receptor (Kharitonenkov et al., 2008). This complex is primarily localized in metabolically active tissues such as the liver and adipose tissue, where its activation stimulates glucose uptake, lipid oxidation, and thermogenesis. In the context of disease, the FGFR1c-KLB pathway is often impaired or insufficient to counteract the metabolic stress associated with obesity and metabolic dysfunction-associated steatohepatitis (MASH). Therapeutic strategies targeting this complex involve the use of FGF21 mimetics or agonistic antibodies designed to potently activate the receptor, thereby reducing hepatic fat, improving insulin sensitivity, and mitigating fibrosis (Akero Therapeutics, 2023; 89bio, 2023). Clinical trials for drugs like efruxifermin and pegozafermin have demonstrated significant efficacy in treating MASH, highlighting the complex's role as a critical node in metabolic disease management.

Other names

FGF21 receptor complexFGFR1c/beta-Klotho complexFGFR1c-beta-Klotho complexFGFR1c-KLB

Agonism of the FGFR1c-KLB complex to mimic or enhance FGF21 signaling, leading to improved metabolic profiles and reduced liver fat.