Gpnmb Is a Potential Marker for the Visceral Pathology in Niemann-Pick Type C Disease

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.

溶酶体NPC1或NPC2蛋白功能受损，会导致细胞内游离胆固醇蓄积，这是尼曼-匹克C型(Niemann-Pick type C, NPC)病的核心致病缺陷。此外，糖鞘脂(glycosphingolipids, GSLs)同样会在溶酶体中蓄积。溶酶体内脂质蓄积可激活一系列基因，其中包含潜在的生物标志物。已有研究证实，Gpnmb的转录水平在NPC小鼠模型的多种组织中均存在上调。我们推测，Gpnmb可作为NPC病内脏脂质蓄积的标志物。本研究显示，Npc1nih/nih小鼠内脏巨噬细胞内的Gpnmb蛋白表达水平升高。值得注意的是，小鼠血浆及NPC患者血浆中可溶性Gpnmb的水平同样升高。将RAW264.7巨噬细胞暴露于诱导NPC表型的药物U18666A后，Gpnmb的表达亦会上调。使用葡萄糖神经酰胺合酶(glucosylceramide synthase, GCS)抑制剂N-丁基-1-脱氧野尻霉素抑制GSL合成，可阻断U18666A诱导的Gpnmb表达上调与分泌。综上，本研究证实Gpnmb在NPC小鼠及患者体内均存在表达上调，这一现象极有可能由GSL蓄积所介导。