Endocrine FGFs: Evolution, Physiology, Pathophysiology, and Pharmacotherapy.
Endocrine FGFs: Evolution, Physiology, Pathophysiology, and Pharmacotherapy.
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DOI：
10.3389/fendo.2015.00154
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发表时间：
2015
影响因子：
5.2
通讯作者：
Konishi M
中科院分区：
文献类型：
--
作者：
Itoh N;Ohta H;Konishi M
人成纤维细胞生长因子 (FGF) 家族包含 22 种结构相关的多肽，它们在神经元功能、发育和代谢中发挥着至关重要的作用。根据作用机制，FGF 可分为内分泌型、旁分泌型和内分泌型 FGF。旁分泌和内分泌 FGF 是通过细胞表面 FGF 受体 (FGFR) 发挥作用而分泌的信号分子。旁分泌 FGF 需要硫酸乙酰肝素作为 FGFR 的辅助因子。相反，内分泌 FGF（包括 FGF19、FGF21 和 FGF23）需要 α-Klotho 或 β-Klotho 作为 FGFR 的辅助因子。脊椎动物特有的内分泌 FGF 在早期脊椎动物进化过程中失去了硫酸乙酰肝素的结合亲和力，并获得了具有 α-Klotho 或 β-Klotho 的系统信号系统。内分泌 FGF 敲除小鼠的表型表明它们在代谢中发挥作用，包括胆汁酸、能量和磷酸盐/活性维生素 D 代谢。内分泌FGF参与人类遗传和代谢疾病的积累证据也表明了它们在代谢疾病中的病理生理作用、代谢疾病的潜在危险因素以及代谢疾病的有用生物标志物。目前正在开发内分泌 FGF 的治疗用途。这些发现为内分泌 FGF 的生理和病理生理作用以及代谢疾病的潜在诊断和治疗策略提供了新的见解。
The human fibroblast growth factor (FGF) family comprises 22 structurally related polypeptides that play crucial roles in neuronal functions, development, and metabolism. FGFs are classified as intracrine, paracrine, and endocrine FGFs based on their action mechanisms. Paracrine and endocrine FGFs are secreted signaling molecules by acting via cell-surface FGF receptors (FGFRs). Paracrine FGFs require heparan sulfate as a cofactor for FGFRs. In contrast, endocrine FGFs, comprising FGF19, FGF21, and FGF23, require α-Klotho or β-Klotho as a cofactor for FGFRs. Endocrine FGFs, which are specific to vertebrates, lost heparan sulfate-binding affinity and acquired a systemic signaling system with α-Klotho or β-Klotho during early vertebrate evolution. The phenotypes of endocrine FGF knockout mice indicate that they play roles in metabolism including bile acid, energy, and phosphate/active vitamin D metabolism. Accumulated evidence for the involvement of endocrine FGFs in human genetic and metabolic diseases also indicates their pathophysiological roles in metabolic diseases, potential risk factors for metabolic diseases, and useful biomarkers for metabolic diseases. The therapeutic utility of endocrine FGFs is currently being developed. These findings provide new insights into the physiological and pathophysiological roles of endocrine FGFs and potential diagnostic and therapeutic strategies for metabolic diseases.