Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, metabolism, and disease

Abstract

Fibroblast growth factors (Fgfs) are proteins with diverse functions in development, repair, and metabolism. The human Fgf gene family with 22 members can be classified into three groups, canonical, intracellular, and hormone-like Fgf genes. In contrast to canonical and intracellular Fgfs identified in invertebrates and vertebrates, hormone-like Fgfs, Fgf15/19, Fgf21, and Fgf23, are vertebrate-specific. The ancestral gene of hormone-like Fgfs was generated from the ancestral gene of canonical Fgfs by gene duplication early in vertebrate evolution. Later, Fgf15/19, Fgf21, and Fgf23 were generated from the ancestral gene by genome duplication events. Canonical Fgfs act as autocrine/paracrine factors in an Fgf receptor (Fgfr)-dependent manner. In contrast, hormone-like Fgfs act as endocrine factors in an Fgfr-dependent manner. Canonical Fgfs have a heparin-binding site necessary for the stable binding of Fgfrs and local signaling. In contrast, hormone-like Fgfs acquired endocrine functions by reducing their heparin-binding affinity during their evolution. Fgf15/19 and Fgf23 require βKlotho and αKlotho as cofactors, respectively. However, Fgf21 might physiologically require neither. Hormone-like Fgfs play roles in metabolism at postnatal stages, although they also play roles in development at embryonic stages. Fgf15/19 regulates bile acid metabolism in the liver. Fgf21 regulates lipid metabolism in the white adipose tissue. Fgf23 regulates serum phosphate and active vitamin D levels. Fgf23 signaling disorders caused by hereditary diseases or tumors result in metabolic disorders. In addition, serum Fgf19 or Fgf21 levels are significantly increased by metabolic disorders. Hormone-like Fgfs are newly emerging and quite unique in their evolution and function.

Fig. 1

Evolutionary history of the Fgf gene family. Fgf13-like is an ancestral gene of the Fgf family. Fgf4-like is an ancestral gene of the canonical Fgf family. Fgf4-like was generated from Fgf13-like by gene duplication. Fgf15/19-like, an ancestral gene of the hormone-like Fgf subfamily, was generated from Fgf4-like by local gene duplication early in vertebrate evolution. Later, Fgf15/19, Fgf21, and Fgf23 were generated by two large-scale genome duplication events during the evolution of early vertebrates

Fig. 2

Action mechanisms of hormone-like Fgfs and regulatory mechanisms of their gene expression. (Fgf15) Intestinal Fgf15 expression is regulated by bile acid produced in the liver. The ligand-bound FXR forms a heterodimer with RXRs and induces the expression of Fgf15. The Fgf15 suppresses the expression of Cyp7a1 in the liver by activating the βKlotho-Fgfr4 complex. The regulatory process forms a negative feedback loop in the regulation of bile acid homeostasis by Fgf15. (Fgf21) Hepatic Fgf21 expression is induced by the activation of PPARα. NEFA binds to and activates PPARα. The ligand-bound PPARα forms a heterodimer with RXRs and induces the expression of Fgf21. However, the regulatory mechanism of Fgf21 expression remains unclear. (Fgf23) Active vitamin D binds the vitamin D receptor (VDR). The ligand-bound VDR forms a heterodimer with retinoid X receptors (RXRs) and induces the expression of Fgf23. The increased Fgf23 suppresses the expression of Cyp27b1 and induces the expression of Cyp24 by activating the αKlotho-Fgfr1c complex. The regulatory process forms a negative feedback loop in the regulation of vitamin D homeostasis