Megalin is a receptor for apolipoprotein M, and kidney-specific megalin-deficiency confers urinary excretion of apolipoprotein M
Megalin is a receptor for apolipoprotein M, and kidney-specific megalin-deficiency confers urinary excretion of apolipoprotein M
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DOI：
10.1210/me.2005-0209
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发表时间：
2006-01-01
影响因子：
--
通讯作者：
Nielsen, LB
中科院分区：
文献类型：
--
作者：
Faber, K;Hvidberg, V;Nielsen, LB
载脂蛋白（apo） M是一种新型载脂蛋白，属于脂钙蛋白超家族，即结合小亲脂化合物的蛋白质。像其他载脂蛋白一样，它在肝细胞中表达并分泌到血浆中，与高密度脂蛋白颗粒结合。此外，apoM在肾小管细胞中也有高水平表达。在这项研究中，我们发现在肾近端小管细胞中表达的多配体受体meggalin是apoM的受体，并介导其在肾脏中的摄取。为了检验apoM与巨噬蛋白的结合，我们在大肠杆菌中表达了一个重组apoM，并将其用于表面等离子体共振和细胞培养研究。结果表明，apoM与固定化meggalin结合[解离常数（K-d）近似于0.3-1 μ M]，并在培养的大鼠卵黄囊细胞中以meggalin依赖的方式被内吞。为了检验巨噬巨噬蛋白在体内结合apoM的重要性，我们分析了肾脏组织特异性巨噬巨噬蛋白缺乏的小鼠。meggalin缺乏与尿中明显的apoM排泄有关，而在正常小鼠、人类或大鼠尿液中未检测到apoM。凝胶过滤分析显示，尿载脂蛋白颗粒小，缺乏载脂蛋白a -1。结果表明，apoM与巨噬蛋白结合，巨噬蛋白介导的肾近端小管内吞作用可阻止apoM通过尿液排出。
Apolipoprotein ( apo) M is a novel apolipoprotein belonging to the lipocalin protein superfamily, i.e. proteins binding small lipophilic compounds. Like other apolipoproteins, it is expressed in hepatocytes and secreted into plasma where it associates with high-density lipoprotein particles. In addition, apoM is expressed at high levels in the kidney tubule cells. In this study, we show that the multiligand receptor megalin, which is expressed in kidney proximal tubule cells, is a receptor for apoM and mediates its uptake in the kidney. To examine apoM binding to megalin, a recombinant apoM was expressed in Escherichia coli and used in surface plasmon resonance and cell culture studies. The results showed apoM binding to immobilized megalin [ dissociation constant ( K-d) similar to 0.3-1 mu M] and that the apoM was endocytosed by cultured rat yolk sac cells in a megalin-dependent manner. To examine the importance of apoM binding by megalin in vivo, we analyzed mice with a tissue-specific deficiency of megalin in the kidney. Megalin deficiency was associated with pronounced urinary excretion of apoM, whereas apoM was not detected in normal mouse, human, or rat urine. Gel filtration analysis showed that the urinary apoM-containing particles were small and devoid of apoA-1. The results suggest that apoM binds to megalin and that megalin-mediated endocytosis in kidney proximal tubules prevents apoM excretion in the urine.