Institute of Agricultural and Nutritional Science, Martin Luther University Halle-Wittenberg, 06120, Halle (Saale), Germany.
Department of Physiology, University of Hohenheim, Garbenstraße 30, 70599, Stuttgart, Germany.
Pflugers Arch. 2020 Apr;472(4):503-511. doi: 10.1007/s00424-020-02363-8. Epub 2020 Mar 18.
Bone cells secrete fibroblast growth factor 23 (FGF23), a hormone that inhibits the synthesis of active vitamin D (1,25(OH)D) and induces phosphate excretion in the kidney. In addition, it exerts paracrine effects on other cells including hepatocytes, cardiomyocytes, and immune cells. The production of FGF23 is controlled by different factors including parathyroid hormone, 1,25(OH)D, alimentary phosphate, insulin, inflammation, and AMP-dependent kinase (AMPK) regulation of store-operated Ca entry (SOCE). Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor with anti-inflammatory properties regulating lipid metabolism. Fibrates, PPARα agonists, are used in the treatment of dyslipidemia and activate AMPK. Here, we tested whether PPARα is a regulator of FGF23. Fgf23 gene expression was analyzed in UMR106 rat osteoblast-like cells by qRT-PCR, AMPK phosphorylation by Western blotting, and SOCE assessed by fluorescence optics. PPARα agonists fenofibrate and WY-14643 suppressed, whereas PPARα antagonist GW6471 and siRNA-mediated knockdown of PPARα induced Fgf23 gene expression. Fenofibrate induced AMPK activity in UMR106 cells and lowered SOCE. AMPK inhibitor compound C abrogated the PPARα effect on FGF23 in large part. Silencing of Orai-1 resulted in failure of PPARα to significantly influence Fgf23 expression. Taken together, PPARα is a potent regulator of FGF23. PPARα agonists down-regulate FGF23 formation at least in part through AMPK-mediated suppression of SOCE.
成骨细胞分泌成纤维细胞生长因子 23（FGF23），一种激素，它抑制活性维生素 D（1,25（OH）D）的合成并诱导肾脏中磷酸盐的排泄。此外，它对包括肝细胞、心肌细胞和免疫细胞在内的其他细胞发挥旁分泌作用。FGF23 的产生受多种因素控制，包括甲状旁腺激素、1,25（OH）D、饮食磷酸盐、胰岛素、炎症和 AMP 依赖性激酶（AMPK）调节的储存操作钙内流（SOCE）。过氧化物酶体增殖物激活受体α（PPARα）是一种具有抗炎特性的转录因子，调节脂代谢。贝特类药物、PPARα 激动剂，用于治疗血脂异常并激活 AMPK。在这里，我们测试了 PPARα 是否是 FGF23 的调节剂。通过 qRT-PCR 分析 UMR106 大鼠成骨样细胞中 Fgf23 基因的表达，通过 Western blot 分析 AMPK 磷酸化，通过荧光光学评估 SOCE。PPARα 激动剂非诺贝特和 WY-14643 抑制，而 PPARα 拮抗剂 GW6471 和 siRNA 介导的 PPARα 敲低诱导 Fgf23 基因表达。非诺贝特诱导 UMR106 细胞中 AMPK 活性并降低 SOCE。AMPK 抑制剂化合物 C 部分阻断了 PPARα 对 FGF23 的作用。敲低 Orai-1 导致 PPARα 无法显著影响 Fgf23 表达。总之，PPARα 是 FGF23 的有效调节剂。PPARα 激动剂通过 AMPK 介导的 SOCE 抑制至少部分地下调 FGF23 的形成。
