Circulating FABP4 is eliminated by the kidney via glomerular filtration followed by megalin-mediated reabsorption

Suman Shrestha,Shoji Kuwahara,Yoshito Tsushima,Aiko Yamaguchi,Tetsuo Machida,Kiyomi Nakajima,Masahiko Kurabayashi,Tatsuya Iso,Yogi Umbarawan,Hirofumi Hanaoka,Akihiko Saito,Masami Murakami,Hiroaki Sunaga

doi:10.1038/s41598-018-34902-w

Abstract

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 125I-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.

Highlights

Fatty acid binding protein 4 (FABP4, known as adipocyte FABP or aP2) is a member of FABP family (14– 15 kDa proteins) and abundantly expressed in adipocytes and macrophages[1,2]
AF647-fatty acid binding protein 4 (FABP4) was exclusively accumulated in the apical membrane of proximal tubule epithelial cells (PTECs) that are detected by Lotus Tetragonolobus Lectin (LTL), a marker for PTECs (Fig. 2)
We showed in this study that majority of circulating FABP4, produced and secreted from adipocytes, is eliminated by the kidney

Summary

Introduction

Fatty acid binding protein 4 (FABP4, known as adipocyte FABP or aP2) is a member of FABP family (14– 15 kDa proteins) and abundantly expressed in adipocytes and macrophages[1,2]. It is likely that circulating FABP4 levels are regulated by three major factors: production in adipocytes, enhanced secretion via lipolysis and disposal probably via the kidney. It has been proposed that most filtered plasma proteins are reabsorbed by the mechanism mediated by megalin and its associated molecule cubilin that are expressed in the apical membranes of proximal tubule epithelial cells (PTECs)[13,14]. Plenty of small proteins including circulating FABP116, a member of FABP family secreted from liver, have been suggested to be reabsorbed by PTECs via megalin-dependent system[13,17,18,19,20]. We conclude that kidney is a key organ for clearance of circulating FABP4 via glomerular filtration of FABP4 and subsequent reabsorption by megalin-mediated endocytosis

Methods

Results

Conclusion