Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease.
Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease.
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DOI：
10.1371/journal.pone.0147208
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
van Eijk M
中科院分区：
文献类型：
--
作者：
Marques AR;Gabriel TL;Aten J;van Roomen CP;Ottenhoff R;Claessen N;Alfonso P;Irún P;Giraldo P;Aerts JM;van Eijk M
NPC1或NPC2溶酶体蛋白功能受损导致未酯化胆固醇在细胞内积聚，这是导致NPC1或NPC2溶酶体蛋白功能受损的主要缺陷。此外，糖鞘糖脂(GSLS)也在溶酶体中积累。溶酶体内脂质的积累触发了一组基因的激活，包括潜在的生物标记物。在鼻咽癌小鼠模型的不同组织中，GPNMB的转录水平已经被证明是升高的。我们推测，GPNMB可作为鼻咽癌内脏脂质蓄积的标志物。我们报道了Npc1nih/NIH小鼠内脏巨噬细胞中GPNMB蛋白水平的表达增加。有趣的是，在小鼠和鼻咽癌患者血浆中也发现了可溶性GPNMB的增加。将RAW264.7巨噬细胞暴露于鼻咽癌表型诱导药物U18666A也上调了GPNMB的表达。用葡萄糖神经酰胺合成酶(GCS)抑制剂N-丁基-1-脱氧诺吉霉素抑制GSL的合成可阻止U18666A诱导的GPNMB的诱导和分泌。综上所述，我们发现GPNMB在鼻咽癌小鼠和患者中上调，很可能是由于GSL的积累。
Impaired function of NPC1 or NPC2 lysosomal proteins leads to the intracellular accumulation of unesterified cholesterol, the primary defect underlying Niemann-Pick type C (NPC) disease. In addition, glycosphingolipids (GSLs) accumulate in lysosomes as well. Intralysosomal lipid accumulation triggers the activation of a set of genes, including potential biomarkers. Transcript levels of Gpnmb have been shown to be elevated in various tissues of an NPC mouse model. We speculated that Gpnmb could serve as a marker for visceral lipid accumulation in NPC disease. We report that Gpnmb expression is increased at protein level in macrophages in the viscera of Npc1nih/nih mice. Interestingly, soluble Gpnmb was also found to be increased in murine and NPC patient plasma. Exposure of RAW264.7 macrophages to the NPC-phenotype-inducing drug U18666A also upregulated Gpnmb expression. Inhibition of GSL synthesis with the glucosylceramide synthase (GCS) inhibitor N-butyl-1-deoxynojirimycin prevented U18666A-induced Gpnmb induction and secretion. In summary, we show that Gpnmb is upregulated in NPC mice and patients, most likely due to GSL accumulation.