Alkyl-glycerol rescues plasmalogen levels and pathology of ether-phospholipid deficient mice.
Alkyl-glycerol rescues plasmalogen levels and pathology of ether-phospholipid deficient mice.
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DOI：
10.1371/journal.pone.0028539
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Wanders RJ
中科院分区：
文献类型：
--
作者：
Brites P;Ferreira AS;da Silva TF;Sousa VF;Malheiro AR;Duran M;Waterham HR;Baes M;Wanders RJ
由过氧化物酶体代谢受损引起的缩醛磷脂缺乏会影响成年期的正常发育和多个器官。旨在恢复血浆酶原水平的治疗选择可能与过氧化物酶体和非过氧化物酶体疾病的治疗相关。在这项研究中，我们确定了一种烷基甘油（AG），即1-O-十八烷基-外消旋-甘油，作为缩醛磷脂合成缺陷的治疗剂的体内疗效。为了实现这一点，Pex 7基因敲除小鼠（一种以不存在缩醛磷脂为特征的1型点状根肢软骨发育不良的小鼠模型）和WT小鼠喂食对照饲料或含有2%烷基甘油的饲料。测定靶器官中的血浆酶原水平，并将生化数据与受影响器官的组织学分析相关联。饲喂AG饲料2个月的Pex 7 KO小鼠的所有外周组织中的缩醛磷脂原水平标准化为饲喂AG的WT小鼠的水平。在饲喂AG饮食的Pex 7 KO小鼠的神经组织中，与对照饲喂KO小鼠相比，血浆酶原水平显著增加。靶器官的组织学分析显示，AG饮食能够阻止睾丸、脂肪组织和哈氏腺中病理学的进展。有趣的是，后者组织的特征在于存在脂滴，当醚磷脂缺乏时，脂滴不存在或尺寸和数量减少，但可以用AAG处理恢复。此外，周围神经的神经传导得到改善。当在发生主要病理变化之前给予时，AG饮食预防或改善了在Pex 7 KO小鼠中观察到的病理，这取决于缩醛磷脂恢复的程度。本研究提供了用烷基甘油治疗缩醛磷脂缺乏症的有益效果的证据。
A deficiency of plasmalogens, caused by impaired peroxisomal metabolism affects normal development and multiple organs in adulthood. Treatment options aimed at restoring plasmalogen levels may be relevant for the therapy of peroxisomal and non-peroxisomal disorders. In this study we determined the in vivo efficacy of an alkyl glycerol (AG), namely, 1-O-octadecyl-rac-glycerol, as a therapeutic agent for defects in plasmalogen synthesis. To achieve this, Pex7 knockout mice, a mouse model for Rhizomelic Chondrodysplasia Punctata type 1 characterized by the absence of plasmalogens, and WT mice were fed a control diet or a diet containing 2% alkyl-glycerol. Plasmalogen levels were measured in target organs and the biochemical data were correlated with the histological analysis of affected organs. Plasmalogen levels in all peripheral tissues of Pex7 KO mice fed the AG diet for 2 months normalized to the levels of AG fed WT mice. In nervous tissues of Pex7 KO mice fed the AG-diet, plasmalogen levels were significantly increased compared to control fed KO mice. Histological analysis of target organs revealed that the AG-diet was able to stop the progression of the pathology in testis, adipose tissue and the Harderian gland. Interestingly, the latter tissues are characterized by the presence of lipid droplets which were absent or reduced in size and number when ether-phospholipids are lacking, but which can be restored with the AAG treatment. Furthermore, nerve conduction in peripheral nerves was improved. When given prior to the occurrence of major pathological changes, the AG-diet prevented or ameliorated the pathology observed in Pex7 KO mice depending on the degree of plasmalogen restoration. This study provides evidence of the beneficial effects of treating a plasmalogen deficiency with alkyl-glycerol.
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影响因子：
4.8
作者：
de Vet, ECJM;Ijlst, L;van den Bosch, H
通讯作者：
van den Bosch, H
影响因子：
4.1
作者：
HORIE, S;SUGA, T
通讯作者：
SUGA, T
影响因子：
3.6
作者：
Allen, Naomi E.;Grace, Philip B.;Key, Timothy
通讯作者：
Key, Timothy
影响因子：
14.5
作者：
Brites, Pedro;Mooyer, Petra A. W.;Wanders, Ronald J. A.
通讯作者：
Wanders, Ronald J. A.
DOI：
10.1073/pnas.0806066105
发表时间：
2008-11-18
影响因子：
11.1
作者：
Ferdinandusse, Sacha;Zomer, Anna W. M.;Brites, Pedro
通讯作者：
Brites, Pedro