Plasmalogen deficiency in cerebral adrenoleukodystrophy and its modulation by lovastatin
Plasmalogen deficiency in cerebral adrenoleukodystrophy and its modulation by lovastatin
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DOI：
10.1111/j.1471-4159.2008.05513.x
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发表时间：
2008-08-01
影响因子：
4.7
通讯作者：
Singh, Inderjit
中科院分区：
文献类型：
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作者：
Khan, Mushfiquddin;Singh, Jaspreet;Singh, Inderjit
在脑肾上腺白质营养不良（cALD）中，长链脂肪酸的积累源于过氧化物酶体ALD蛋白（ALDP）的缺陷，导致髓磷脂/少突胶质细胞的损失，诱导炎症性疾病和精神退化。在cALD患者的脑白质中，我们不仅观察到超长链脂肪酸水平升高，而且还观察到血浆乙醇胺（PlsEtn）水平降低和活性氧（ROS）水平升高。PlsEtn在斑块区域的损失最大，在cALD脑的组织学上看起来正常的区域损失较小，但意义重大。PlsEtn的减少与氧化应激有关，在cALD脑的所有区域，活性脂质醛（4-羟基壬烯醛和丙烯醛）和有害氧化蛋白（蛋白质羰基）水平的增加支持了这一点。通过对PlsEtn生物合成的关键酶二羟丙酮磷酸酰基转移酶进行基因沉默，进一步支持了PlsEtn水平与活性氧（ROS）之间的反比关系。在ALDP/ ald相关蛋白基因沉默后，体外PlsEtn水平也有所下降。此外，在ALDP敲除（KO）小鼠的脑白质中检测到低水平的PlsEtn。用洛伐他汀治疗ALDP KO小鼠增加了大脑中的PlsEtn水平。此外，在一项体外研究中，洛伐他汀处理大鼠C6胶质细胞增加了PlsEtn的生物合成，减少了细胞因子诱导的ROS积累。综上所述，本研究报告了cALD中PlsEtn和ROS代谢的改变可能通过洛伐他汀治疗得到纠正。
In cerebral adrenoleukodystrophy (cALD), an accumulation of very long chain fatty acids stems from a defect of the peroxisomal ALD protein (ALDP) and results in the loss of myelin/oligodendrocytes, induction of inflammatory disease and mental deterioration. In brain white matter of cALD patients, we observed not only increased levels of very long chain fatty acid but also reduced levels of plasmenylethanolamine (PlsEtn) and increased levels of reactive oxygen species (ROS). The loss of PlsEtn was greatest in the plaque area and lesser but significant at histologically normal-looking areas of the cALD brain. The reduction in PlsEtn was related to oxidative stress, as supported by increased levels of reactive lipid aldehydes (4-hydroxynonenal and acrolein) and deleterious oxidized proteins (protein carbonyl) in all areas of the cALD brain. This inverse relationship between the levels of PlsEtn and reactive oxygen species (ROS) was further supported in an in vitro study using gene-silencing for dihydroxyacetone phosphate-acyl transferase, a key enzyme for PlsEtn biosynthesis. Levels of PlsEtn were also found decreased in vitro following gene-silencing for the ALDP/ALD-related protein. Furthermore, low levels of PlsEtn were detected in brain white matter of ALDP knock out (KO) mice. A treatment of ALDP KO mice with lovastatin increased PlsEtn levels in the brain. Further, in an in vitro study, lovastatin treatment of rat C6 glial cells increased PlsEtn biosynthesis and reduced the cytokine-induced ROS accumulation. In summary, this study reports that altered metabolism of PlsEtn and ROS in cALD may be corrected by lovastatin treatment.