Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland; Department of Ophthalmology, Kuopio University Hospital, P.O. Box 100, FI-70029, KYS, Finland.
Cell Signal. 2017 Dec;40:10-21. doi: 10.1016/j.cellsig.2017.08.009. Epub 2017 Aug 24.
FGF21 is a multifunctional metabolic and stress hormone which is normally expressed in liver but cellular stress, e.g. mitochondrial or endoplasmic reticulum (ER) stress, can induce its expression and subsequent secretion from several mammalian tissues. The stress kinases of the integrated stress response (ISR) pathway stimulate the expression of FGF21 through the activation of ATF4 transcription factor, thus enhancing cellular stress resistance. The metabolic and stress-inducible transactivation mechanisms of FGF21 gene are mostly mediated through separate pathways. FGF21 is an interorgan regulator which can alleviate many age-related metabolic and stress disorders, e.g. through the activation of AMPK signaling. FGF21 signaling is also involved in circadian and torpor regulation. Given that circulating FGF21 can attenuate organelle stress, e.g. mitochondrial and ER stresses, it resembles a stress-induced cell non-autonomous regulation of proteostasis and longevity present in model organisms. The overexpression of FGF21 can even extend the lifespan of mice, probably by improving the healthspan. We will clarify the positive and negative signaling mechanisms which control the stress-related expression of FGF21 through the ISR pathway. Moreover, we will examine the role of FGF21 as an interorgan coordinator of survival functions in metabolic and stress disorders. We conclude that FGF21 can be viewed as a cell non-autonomous enhancer of longevity in mammals.
成纤维细胞生长因子 21（FGF21）是一种多功能的代谢和应激激素，通常在肝脏中表达，但细胞应激，如线粒体或内质网（ER）应激，可诱导其在几种哺乳动物组织中的表达和随后的分泌。整合应激反应（ISR）途径的应激激酶通过激活 ATF4 转录因子刺激 FGF21 的表达，从而增强细胞应激抗性。FGF21 基因的代谢和应激诱导的反式激活机制主要通过单独的途径介导。FGF21 是一种器官间调节剂，可通过激活 AMPK 信号通路来缓解许多与年龄相关的代谢和应激紊乱，如通过激活 AMPK 信号通路来缓解许多与年龄相关的代谢和应激紊乱。FGF21 信号通路也参与昼夜节律和蛰伏的调节。鉴于循环中的 FGF21 可以减轻细胞器应激，如线粒体和 ER 应激，它类似于模型生物中存在的应激诱导的细胞非自主性调节蛋白质稳态和寿命的机制。FGF21 的过表达甚至可以延长小鼠的寿命，可能是通过改善健康寿命来实现的。我们将阐明通过 ISR 途径控制 FGF21 应激相关表达的正、负信号机制。此外，我们将研究 FGF21 作为代谢和应激紊乱中生存功能的器官间协调因子的作用。我们得出结论，FGF21 可以被视为哺乳动物中细胞非自主性的长寿增强因子。
