betaKlotho

BetaKlotho, encoded by the KLB gene, is a transmembrane protein in the Klotho family that functions as a co-receptor for fibroblast growth factors FGF19 and FGF21. It does not signal alone but enables high-affinity binding and signaling through fibroblast growth factor receptors (FGFRs).

In humans and other mammals, betaKlotho is expressed in tissues such as the liver, white and brown adipose tissue, and to lesser extents in the pancreas and other organs. It forms tissue-specific receptor complexes: with FGFR4 to mediate FGF19 signaling primarily in the liver, and with FGFR1c to mediate FGF21 signaling in adipose tissue and other sites.

Activation of these complexes triggers FGFR signaling pathways, including MAPK/ERK and PI3K/AKT cascades, leading to regulation of gene expression and metabolic processes. Through FGF19-FGFR4-betaKlotho, betaKlotho influences bile acid synthesis by repressing CYP7A1. Through FGF21-FGFR1c-betaKlotho, it affects glucose and lipid metabolism, energy expenditure, and insulin sensitivity.

Clinical relevance: Genetic variation in KLB has been linked with metabolic traits such as body mass index, lipid levels, and glucose homeostasis in genome-wide association studies. Because betaKlotho is essential for FGF19/FGF21 signaling, it is a focus of research into therapies for obesity, diabetes, and related disorders. Therapeutic strategies include FGF19/FGF21 analogs or agents that modulate KLB expression or function; however, tissue distribution and signaling context influence effectiveness and safety.