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Functional interaction between peroxisomes and cholesterol metabolisms in glial cells

神经胶质细胞中过氧化物酶体和胆固醇代谢之间的功能相互作用

基本信息

批准号：
18590049
负责人：
MORITA Masashi
金额：
$ 2.48万
依托单位：
University of Toyama
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590049/
关键词：
Peroxisome adrenoleukodystrophy ABC protein glial cell cholesterol ABCD1 fatty acid β-oxidation macrophage マクロファージ

项目摘要

1. Adrenoleukodystrophy (X-ALD) is an inherited disorder characterized by progressive demyelination of the central nervous system. X-ALD is due to the mutations in the ABCD1 gem. It encodes a half-size peroxisomal ABC protein, adrenoleukodystrophy protein (ABCD1), which consists of 745 amino acids. ABCD1 contains a transmembrane and an ATP-binding domain(s), and is supposed to work after dimerization. Among missense mutations in X-ALD patients, more than 70% of the mutant ABCD1s were not detected by immunoblot analysis. We examined intracellular fate of 9 mutant ABCD1s with missense mutation. We have found that not only dysfunction of mutant ABCD1 but also mistargeting as well as degradation of mutant ABCD1s would be associated with X-ALD. Furthermore, we found for the fast time that mutant ABCD1s were degraded rapidly by proteasomes.2. Dysfunction of ABCD1 leads to the accumulation of very long chain fatty acids (VLCFA) in total body fluids, especially in brain. ABCD1 has been thought … More to be a transporter of VLCFA or VLCFA-CoA, but the precise function is still unclear. To investigate the roles of ABCD1 in lipid metabolisms in glial cells, we prepared ABCD1-knockdown glioblastoma cells and ABCD 1-knockout mouse primary astrocytes, and analyzed the VLCFA and cholesterol metabolisms in these cells. This study shows that dysfunction of ABCD1 results in the up-regulation of fatty acid elongases as well as the reduction of peroxisomal VLCFA β-oxidation in glial cells. Disruption of these VLCFA metabolisms might result in the VLCFA accumulation in X-ALD brain. Furthermore, cholesterol level was significantly decreased in ABCD1-knockdown glioblastoma cells.In ABCD1-knockdown THP-1 macrophage, incorporation of cholesterol into macrophage was decreased and ApoAI-dependent cholesterol efflux was increased. In addition, ApoE secretion into medium and cholesterol synthesis was significantly increased. These results suggest that cholesterol efflux was inc eased by the dysfunction of ABCD1 in THP-1 macrophage.Although the functional interaction between ABCD1 and cholesterol metabolisms remains to be determined, ABCD1 might have a role for maintaining the cellular cholesterol homeostasis both in glial cells and macrophage. The disturbed cholesterol as well as VLCFA metabolisms in glial cells might be related to the neurodegeneration in X-ALD. Less

1.肾上腺脑白质营养不良（X-ALD）是一种以中枢神经系统进行性脱髓鞘为特征的遗传性疾病。X-ALD是由于ABCD 1基因突变引起的。它编码一半大小的过氧化物酶体ABC蛋白，肾上腺脑白质营养不良蛋白（ABCD 1），由745个氨基酸组成。ABCD 1包含一个跨膜和一个ATP结合结构域，并且应该在二聚化后起作用。在X-ALD患者的错义突变中，超过70%的突变ABCD1s未被免疫印迹分析检测到。我们研究了9个突变ABCD 1错义突变的细胞内命运。我们已经发现，不仅突变ABCD 1的功能障碍，而且突变ABCD 1 s的错误定位以及降解与X-ALD相关。此外，我们发现突变ABCD1s在短时间内被蛋白酶体迅速降解. ABCD 1的功能障碍导致极长链脂肪酸（VLCFA）在总体液中的积累，特别是在大脑中。ABCD1被认为是 ...更多信息是VLCFA或VLCFA-CoA的转运蛋白，但其确切功能尚不清楚。为了研究ABCD 1在胶质细胞脂质代谢中的作用，我们制备了ABCD 1敲除的胶质母细胞瘤细胞和ABCD 1敲除的小鼠原代星形胶质细胞，并分析了这些细胞中的VLCFA和胆固醇代谢。这项研究表明，ABCD 1的功能障碍导致神经胶质细胞中脂肪酸延长酶的上调以及过氧化物酶体VLCFA β-氧化的减少。这些VLCFA代谢的破坏可能导致VLCFA在X-ALD脑中积聚。在ABCD 1敲低的THP-1巨噬细胞中，胆固醇向巨噬细胞的掺入减少，ApoAI依赖的胆固醇流出增加。此外，Apoe向培养基中的分泌和胆固醇合成显着增加。这些结果表明，THP-1巨噬细胞中ABCD 1功能障碍可导致胆固醇流出增加，虽然ABCD 1与胆固醇代谢之间的功能相互作用尚不清楚，但ABCD 1可能在维持胶质细胞和巨噬细胞胆固醇稳态中起作用。胶质细胞胆固醇代谢紊乱和VLCFA代谢紊乱可能与X-ALD的神经变性有关。少

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Evaluation of the role of the endoplasmic reticulum-Golgi transit in the biogenesis of peroxisomal membrane proteins in wild type and peroxisomal biogenesis mutant CHO cells.

评估内质网-高尔基体转运在野生型和过氧化物酶体生物发生突变体 CHO 细胞中过氧化物酶体膜蛋白生物发生中的作用。

DOI：
发表时间：
2007
期刊：
Biol. Res. 40
影响因子：
0
作者：
Toro A.;Arredondo C.;Cordova G.;Araya C.;Palacios J. L.;Venegas A.;Morita;M.;Imanaka T.;and Santos M. J
通讯作者：
and Santos M. J

Adrenoleukodystrophy: subcellular localization and degradation of adrenoleukodystrophy protein(ALDP/ABCDl)with naturally occurring missense mutations.

肾上腺脑白质营养不良：具有自然发生的错义突变的肾上腺脑白质营养不良蛋白（ALDP/ABCD1）的亚细胞定位和降解。

DOI：
发表时间：
2007
期刊：
J. Neurochem 101
影响因子：
0
作者：
Takahashi N.;Morita M.;MaedaT.;Harayama Y.;Shimozawa N.;Suzuki Y.;Furuya H.;Sato R.;Kashiwayama Y;and Imanaka T.
通讯作者：
and Imanaka T.

Role of ABC proteins, ABCD1(ALDP) and ABCD3(P1VIP70) in peroxisomal fatty acid β-oxidation

ABC 蛋白、ABCD1(ALDP) 和 ABCD3(P1VIP70) 在过氧化物酶体脂肪酸 β-氧化中的作用