Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney

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 D3 [1,25(OH)2D] production. Disorders of FGF23 homeostasis are associated with significant morbidity and mortality, but a fund...

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Published in:	The Journal of clinical investigation Vol. 130; no. 3; pp. 1513 - 1526
Main Authors:	Simic, Petra, Kim, Wondong, Zhou, Wen, Pierce, Kerry A, Chang, Wenhan, Sykes, David B, Aziz, Najihah B, Elmariah, Sammy, Ngo, Debby, Pajevic, Paola Divieti, Govea, Nicolas, Kestenbaum, Bryan R, de Boer, Ian H, Cheng, Zhiqiang, Christov, Marta, Chun, Jerold, Leaf, David E, Waikar, Sushrut S, Tager, Andrew M, Gerszten, Robert E, Thadhani, Ravi I, Clish, Clary B, Jüppner, Harald, Wein, Marc N, Rhee, Eugene P
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 01-03-2020
Subjects:	Acute Kidney Injury - genetics Acute Kidney Injury - metabolism Acute Kidney Injury - pathology Acyltransferase Animals Aptamers Biomedical research Bone marrow Calcitriol Cell Line Chromatography Female Fibroblast Growth Factor-23 Fibroblast growth factors Fibroblast Growth Factors - genetics Fibroblast Growth Factors - metabolism Fibroblasts Glycerol Glycerol-3-phosphate Glycerophosphates - metabolism Growth factors Heart surgery Homeostasis Hormones Human subjects Humans Kidney - metabolism Kidney - pathology Kidneys Liquid chromatography Lysophosphatidic acid Male Mass spectrometry Mass spectroscopy Metabolites Metabolomics Mice Mice, Knockout Morbidity Mortality Phosphates Physiological aspects Proteins Proteomics Receptors, Lysophosphatidic Acid - genetics Receptors, Lysophosphatidic Acid - metabolism Renal function Scientific equipment industry Spectroscopy Veins & arteries Vitamin D3 United States Massachusetts Bone Biology Homeostasis Nephrology Bone disease Chronic kidney disease
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Summary:	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 D3 [1,25(OH)2D] 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 Lpar1 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Authorship note: AMT is deceased.
ISSN:	0021-9738 1558-8238
DOI:	10.1172/jci131190