Differences in cleavage of globotriaosylceramide and its derivatives accumulated in organs of young Fabry mice following enzyme replacement therapy
Differences in cleavage of globotriaosylceramide and its derivatives accumulated in organs of young Fabry mice following enzyme replacement therapy
复制标题
DOI：
10.1016/j.ymgme.2016.10.003
复制
发表时间：
2017-01-01
影响因子：
3.8
通讯作者：
Togawa, Tadayasu
中科院分区：
文献类型：
--
作者：
Kodama, Takashi;Tsukimura, Takahiro;Togawa, Tadayasu
在Fabry病中，由于缺乏α-半乳糖苷酶A(GLA)活性，大量的Gb3和相关的神经鞘糖脂积累在器官中。重组GLA的酶替代疗法(ERT)现已问世，据报道，ERT对Fabry病患者是有益的，特别是那些在疾病早期开始治疗的患者。然而，似乎不同器官ERT的效果不同，当ERT开始较晚时，肾脏中积累的Gb3表现出对ERT的抵抗力。在本研究中，我们检测了ERT幼鼠肾脏、肝脏和心脏中Gb3亚型和lyso-Gb3及其类似物的裂解差异。结果表明，反复给予重组GLA对Gb3及其衍生物在器官中积累的降解有显著影响。然而，在肾脏中积累的特定Gb3亚型，即Gb3(C20：0)和Gb3(C24OH)，基本上逃脱了降解。这种Gb3亚型可能会从很小的时候就逐渐在肾脏中积累，这会导致ERT治疗Fabry病的疗效降低。(C)2016 Elsevier Inc.保留所有权利。
In Fabry disease, large amounts of globotriaosylceramide (Gb3) and related glycosphingolipids accumulate in organs due to a deficiency of alpha-galactosidase A (GLA) activity. Enzyme replacement therapy (ERT) with recombinant GLA is now available, and it has been reported that ERT is beneficial for patients with Fabry disease, especially those who start treatment at an early stage of the disease. However, it seems that the efficacy of ERT differs with each organ, and Gb3 accumulated in the kidneys shows resistance to ERT when it is started at a late stage.In this study, we examined the differences in cleavage of Gb3 isoforms, and lyso-Gb3 and its analogues in the kidneys, liver, and heart in young Fabry mice subjected to ERT. The results revealed that recurrent administration of recombinant GLA had prominent effects in terms of degradation of Gb3 and its derivatives accumulated in the organs. However, particular Gb3 isoforms, i.e., Gb3 (C20:0) and Gb3 (C24OH), accumulated in the kidneys largely escaped from degradation. Such Gb3 isoforms may gradually accumulate in the kidneys from a young age, which results in a reduction in the efficacy of ERT for Fabry disease. (C) 2016 Elsevier Inc. All rights reserved.