Mutation of megalin leads to urinary loss of selenoprotein P and selenium deficiency in serum, liver, kidneys and brain
Mutation of megalin leads to urinary loss of selenoprotein P and selenium deficiency in serum, liver, kidneys and brain
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DOI：
10.1042/bj20100779
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发表时间：
2010-10-01
影响因子：
4.1
通讯作者：
Schweizer, Ulrich
中科院分区：
文献类型：
--
作者：
Chiu-Ugalde, Jazmin;Theilig, Franziska;Schweizer, Ulrich
硒在哺乳动物体内的分布是由肝细胞分泌的富硒糖蛋白SePP（selenoprotein P）介导的。遗传和生化证据表明，内吞受体ApoER 2（载脂蛋白E受体2）和巨蛋白介导组织特异性SePP摄取。在本研究中，将巨蛋白突变小鼠饲喂含有足够（0.15 p. p.m.）或偏低（下午0时08分）硒含量和分析组织和血浆硒水平，细胞GPx（谷胱甘肽过氧化物酶）的活动和蛋白质表达模式。Megalin突变小鼠显示尿硒丢失增加，这与尿中SePP排泄相关。因此，血清硒和SePP水平显着降低megalin突变小鼠，达到边缘水平的低硒饮食。此外，肾硒含量和肾硒蛋白的表达相应地减少，因为是SePP内化沿着近端小管上皮。虽然GPx 4的表达在睾丸中没有改变，硒和GPx的活性在肝脏和大脑中显着降低。当喂食低硒饮食时，megalin突变小鼠出现运动协调受损，但没有星形胶质细胞增生。这些结果表明，megalin防止尿SePP损失，并参与脑Se/SePP摄取。
Distribution of selenium (Se) within the mammalian body is mediated by SePP (selenoprotein P), an Se-rich glycoprotein secreted by hepatocytes. Genetic and biochemical evidence indicate that the endocytic receptors ApoER2 (apolipoprotein E receptor 2) and megalin mediate tissue-specific SePP uptake. In the present study megalin-mutant mice were fed on diets containing adequate (0.15 p.p.m.) or low (0.08 p.p.m.) Se content and were analysed for tissue and plasma Se levels, cellular GPx (glutathione peroxidase) activities and protein expression patterns. Megalin-mutant mice displayed increased urinary Se loss, which correlated with SePP excretion in their urine. Accordingly, serum Se and SePP levels were significantly reduced in megalin-mutant mice, reaching marginal levels on the low-Se diet. Moreover, kidney Se content and expression of renal selenoproteins were accordingly reduced, as was SePP internalization along the proximal tubule epithelium. Although GPx4 expression was not altered in testis, Se and GPx activity in liver and brain were significantly reduced. When fed on a low-Se diet, megalin-mutant mice developed impaired movement co-ordination, but no astrogliosis. These findings suggest that megalin prevents urinary SePP loss and participates in brain Se/SePP uptake.