FREE SPHINGOID BASES IN TISSUES FROM PATIENTS WITH TYPE-C NIEMANN-PICK DISEASE AND OTHER LYSOSOMAL STORAGE DISORDERS
FREE SPHINGOID BASES IN TISSUES FROM PATIENTS WITH TYPE-C NIEMANN-PICK DISEASE AND OTHER LYSOSOMAL STORAGE DISORDERS
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DOI：
10.1016/0925-4439(94)90021-3
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发表时间：
1994-05-25
影响因子：
6.2
通讯作者：
VANIER, MT
中科院分区：
文献类型：
--
作者：
RODRIGUEZLAFRASSE, C;ROUSSON, R;VANIER, MT
从Niemann-Pick C型(NPC)小鼠模型结合到正常成纤维细胞培养中添加鞘氨酸所诱导的NPC样表型，肝脏中发现的游离狮身人面像碱基增加了20倍，促使我们调查这些化合物在人类疾病中的潜在参与。用灵敏的高效液相色谱法测定肝、脾、脑和皮肤成纤维细胞中鞘氨醇和鞘氨醇的含量。在鼻咽癌患者的肝和脾中，鞘氨醇和鞘氨酸鞘氨醇在疾病的胎儿期已经显著增加，而在脑组织中没有明显的增加。在皮肤成纤维细胞培养中，也出现了显著的增加，不受溶酶体内游离胆固醇含量的调节。为了研究这些发现的特异性，对其他溶酶体储存障碍进行了研究。A型和B型Niemann-Pick病(神经鞘磷脂酶缺陷型)患者的肝脏和脾组织中有明显的积聚(24~36倍)，而A型Niemann-Pick病患者的大脑皮质中也有明显的积聚。桑德霍夫病中也出现了显著的蓄积，而其他几种鞘脂疾病显示出中度升高。除桑德霍夫病脑外，所有病例的鞘氨醇/鞘氨酸比值均无变化，提示神经鞘糖脂分解代谢所积累的游离神经鞘氨醇碱基是由神经鞘磷脂分解而来。鞘氨醇与溶酶体内堆积的脂类物质形成复合体可能是溶酶体脂代谢的一般机制。然而，在鼻咽癌中，与溶酶体存储程度不成比例的游离狮身人面像碱基的增加以及培养的成纤维细胞的特定参与表明了一种更复杂或联合的机制。
The 20-fold increase of free sphingoid bases found in liver from a murine model of Niemann-Pick type C (NPC) combined to the NPC-like phenotype induced by addition of sphinganine to normal fibroblast cultures prompted us to investigate the potential involvement of these compounds in the human disease. The contents of sphingosine and sphinganine were measured in liver, spleen, brain and skin fibroblast cultures by a sensitive HPLC method. In liver and spleen from NPC patients, a 6- to 24-fold elevation of sphingosine and sphinganine already prominent at the fetal stage of the disease was observed, while no clear increase could be evidenced in brain tissue. A significant increase, not modulated by the intralysosomal content of free cholesterol, also occurred in skin fibroblast cultures. To investigate the specificity of these findings, other lysosomal storage disorders were studied. A striking accumulation was found in liver and spleen (24- to 36-fold) from patients with Niemann-Pick disease type A and B (sphingomyelinase-deficient forms), and in cerebral cortex of type A Niemann-Pick disease. A significant storage also occurred in Sandhoff disease, while several other sphingolipidoses showed a moderate elevation. In all cases but Sandhoff disease brain, the sphingosine/sphinganine ratio remained unchanged, suggesting that the accumulated free sphingoid bases derived from sphingolipid catabolism. Formation of complexes between sphingosine and the lipid material accumulated in lysosomes might be a general mechanism in lysosomal lipidoses. In NPC, however, an increase of free sphingoid bases disproportionate to the degree of lysosomal storage and a specific involvement of cultured fibroblasts suggested a more complex or combined mechanism.