Abstract
Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, and endocrine FGF subfamilies. FGF19, FGF21, and FGF23 belong to the hormone-like/endocrine FGF subfamily. These endocrine FGFs are mainly associated with the regulation of cell metabolic activities such as homeostasis of lipids, glucose, energy, bile acids, and minerals (phosphate/active vitamin D). Endocrine FGFs function through a unique protein family called klotho. Two members of this family, α-klotho, or β-klotho, act as main cofactors which can scaffold to tether FGF19/21/23 to their receptor(s) (FGFRs) to form an active complex. There are ongoing studies pertaining to the structure and mechanism of these individual ternary complexes. These studies aim to provide potential insights into the physiological and pathophysiological roles and therapeutic strategies for metabolic diseases. Herein, we provide a comprehensive review of the history, structure–function relationship(s), downstream signaling, physiological roles, and future perspectives on endocrine FGFs.
Highlights
The fibroblast growth factor (FGF) family comprises twenty-two members that share a similar core protein sequence and structure, but each subfamily exhibits a wide range of biological functions [1]
The results indicate that FGF21 mediates glucose homeostasis through peroxisome proliferator-activated receptor α (PPARα) which is a master regulator coordinating metabolic adaptions to fasting and starvation [48]
Treatment with FGF19 regained the normal glucose tolerance. These findings provided a piece of evidence for a new physiological role of FGF19 in glucose homeostasis [5,80]
Summary
The fibroblast growth factor (FGF) family comprises twenty-two members that share a similar core protein sequence and structure, but each subfamily exhibits a wide range of biological functions [1]. Their molecular masses range from 17 kDa to 34 kDa [2]. Β-Klotho (KLB) augments the FGF19 signaling by binding to FGFR4, and FGF21 to FGFR1c, whereas FGF23 activates the signaling complex composed of FGFR1c and α-Klotho (KLA) [9] They have evolved to regulate metabolisms of bile acids, phosphates, carbohydrates, and lipids in addition to their canonical FGF functions [3,5]. We attempt to provide a comprehensive account of the progress in the research on the structure, signaling, physiological roles, and therapeutic applications of endocrine FGFs
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