Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan.
Sci Rep. 2018 Nov 6;8(1):16451. doi: 10.1038/s41598-018-34902-w.
Circulating fatty acid binding protein 4 (FABP4), secreted from adipocytes, is a potential biomarker for metabolic and cardiovascular diseases. Circulating FABP4 levels are positively associated with adiposity and adrenergic stimulation, but negatively with renal function. In this study, we addressed the issue of how the kidney regulates clearance of circulating FABP4. Tracing study revealed remarkable accumulation of I-labeled FABP4 in the kidney. Exogenous FABP4 was exclusively detected in the apical membrane of proximal tubule epithelial cells (PTECs). Bilateral nephrectomy resulted in marked elevation of circulating FABP4 levels. Accelerated lipolysis by β-3 adrenergic stimulation led to a marked elevation in circulating FABP4 in mice with severe renal dysfunction. Megalin, an endocytic receptor expressed in PTECs, plays a major role in reabsorption of proteins filtered through glomeruli. Quartz-crystal microbalance study revealed that FABP4 binds to megalin. In kidney-specific megalin knockout mice, a large amount of FABP4 was excreted in urine while circulating FABP4 levels were significantly reduced. Our data suggest that circulating FABP4 is processed by the kidney via the glomerular filtration followed by megalin-mediated reabsorption. Thus, it is likely that circulating FABP4 levels are determined mainly by balance between secretion rate of FABP4 from adipocytes and clearance rate of the kidney.
循环脂肪酸结合蛋白 4（FABP4），由脂肪细胞分泌，是代谢和心血管疾病的潜在生物标志物。循环 FABP4 水平与肥胖和肾上腺素刺激呈正相关，但与肾功能呈负相关。在这项研究中，我们研究了肾脏如何调节循环 FABP4 的清除。示踪研究显示 I 标记的 FABP4 在肾脏中明显积聚。外源性 FABP4 仅在近端肾小管上皮细胞（PTECs）的顶膜中检测到。双侧肾切除术后，循环 FABP4 水平显著升高。β-3 肾上腺素刺激导致脂解加速，严重肾功能障碍的小鼠循环 FABP4 水平显著升高。在 PTECs 中表达的内吞受体 megalin 在肾小球滤过的蛋白质重吸收中起主要作用。石英晶体微天平研究表明 FABP4 与 megalin 结合。在肾脏特异性 megalin 敲除小鼠中，大量 FABP4 从尿液中排泄，而循环 FABP4 水平显著降低。我们的数据表明，循环 FABP4 通过肾脏的肾小球滤过，然后通过 megalin 介导的重吸收进行处理。因此，循环 FABP4 水平可能主要由脂肪细胞分泌 FABP4 的速率和肾脏的清除率之间的平衡决定。
