Physiological and pathophysiological role of endocrine fibroblast growth factors

The endocrine subfamily of fibroblast growth factors (FGF) includes three factors: FGF19, FGF21, FGF23. They act on distal tissues through FGF receptors (FGFRs). The FGFR activation requires two cofactors: α- and β-Klotho, which are structurally related single-pass transmembrane proteins. The endocrine FGFs regulate various metabolic processes involved in the regulation of glucose and lipid metabolism as well as bile acid circulation, vitamin D modulation, and phosphate homeostasis. The FGF-FGFR dysregulation is widely implicated in the pathogenesis of various disorders. Significant alterations in plasma FGF concentration are associated with the most prevalent chronic diseases, including dyslipidemia, type 2 diabetes, cardiovascular diseases, obesity, non-alcoholic fatty liver disease, diseases of the biliary tract, chronic kidney disease, inflammatory bowel disease, osteomalacia, various malignancies, and depression. Therefore, the endocrine FGFs may serve as disease predictors or biomarkers, as well as potential therapeutic targets. Currently, numerous analogues and inhibitors of endocrine FGFs are under development for treatment of various disorders, and recently, a human monoclonal antibody against FGF23 has been approved for treatment of X-linked hypophosphatemia. The aim of this review is to summarize the current data on physiological and pathophysiological actions of the endocrine FGF subfamily and recent research concerning the therapeutic potential of the endocrine FGF pathways.