Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney
Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney
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DOI：
10.1172/jci131190
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发表时间：
2020-03-02
影响因子：
15.9
通讯作者：
Rhee, Eugene P.
中科院分区：
文献类型：
--
作者：
Simic, Petra;Kim, Wondong;Rhee, Eugene P.
成纤维细胞生长因子23(FGF23)是一种骨源性激素，通过增加肾脏磷酸盐排泄和减少1，25-二羟基维生素D-3[1，25(OH)(2)D]的产生来控制血磷水平。FGF23的稳态失调与显著的发病率和死亡率有关，但对FGF23产生的调节缺乏基本的了解。由于肾脏是FGF23作用的主要终末器官，我们假设它释放一种调节FGF23合成的因子。利用基于适体的蛋白质组学和基于LC-MS的代谢组学，我们从受试者的肾静脉血浆中提取了1600多个分子。肾静脉3-磷酸甘油(G-3-P)与循环FGF23相关性最强。在小鼠中，外源性G-3-P通过局部G-3-P酰基转移酶(GPAT)介导的溶血磷脂酸(LPA)合成刺激骨和骨髓FGF23的产生。此外，G-3-P和LPA对FGF23的刺激作用需要LPA受体1(LPAR1)。急性肾损伤(AKI)导致FGF23水平升高，使人和小鼠循环G-3-P迅速增加，其对FGF23的影响可被GPAT抑制或LIMA缺失所抵消。总之，我们的发现确立了肾源性G-3-P在矿物质代谢中的作用，并概述了在肾脏损伤过程中调节FGF23产生的潜在靶点。
Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D] production. Disorders of FGF23 homeostasis are associated with significant morbidity and mortality, but a fundamental understanding of what regulates FGF23 production is lacking. Because the kidney is the major end organ of FGF23 action, we hypothesized that it releases a factor that regulates FGF23 synthesis. Using aptamer-based proteomics and liquid chromatography-mass spectrometry-based (LC-MS-based) metabolomics, we profiled more than 1600 molecules in renal venous plasma obtained from human subjects. Renal vein glycerol-3-phosphate (G-3-P) had the strongest correlation with circulating FGF23. In mice, exogenous G-3-P stimulated bone and bone marrow FGF23 production through local G-3-P acyltransferase-mediated (GPAT-mediated) lysophosphatidic acid (LPA) synthesis. Further, the stimulatory effect of G-3-P and LPA on FGF23 required LPA receptor 1 (LPAR1). Acute kidney injury (AKI), which increases FGF23 levels, rapidly increased circulating G-3-P in humans and mice, and the effect of AKI on FGF23 was abrogated by GPAT inhibition or Lima deletion. Together, our findings establish a role for kidney-derived G-3-P in mineral metabolism and outline potential targets to modulate FGF23 production during kidney injury.