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

• 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

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.肾上腺素肌营养不良（X-Ald）是一种遗传性疾病，其中枢神经系统的进行性脱髓鞘是ABCD1 GEM中的突变。包含X-ald患者中的跨膜和ATP结合域INS，超过70％的突变体ABCD1通过免疫印迹分析检测到我们检查了9个突变体ABCD1的细胞内命运。以及X-ald的降解以及X-ald的降解。成为VLCFA或VLCFA-COA的转运蛋白，但精确的功能仍在研究ABCD1在脂质细胞中的作用。细胞在ABCD1-KNOCKDOWN THP-1巨噬细胞中，胆固醇降低了ABCD1-KNOCKDOWN胶质母细胞中的水平，将胆固醇降低到巨噬细胞中，而APOAI依赖性胆固醇依赖性胆固醇依赖性。通过THP-1的功能障碍，ABCD1和胆固醇代谢之间的功能相互作用仍有待确定胆固醇的胆固醇稳态

项目成果

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。

• 发表时间: 2007
• 期刊: J. Neurochem 101
• 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

• 发表时间: 2007
• 作者: Morita;M;et. al.
• 通讯作者: et. al.

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。

• 发表时间: 2007
• 期刊: Biol. Res. 40
• 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

副腎白質ジストロフィーの分子病態の解明と治療薬開発

肾上腺脑白质营养不良分子病理学的阐明和治疗药物的开发

• 发表时间: 2006
• 作者: 水野聖子;横山佳代;守田雅志;今中常雄;守田雅志
• 通讯作者: 守田雅志

Impaired expression of ALDP, a peroxisomal ABC protein, leads tothe disruption of lipid metabolisms in human glioblastoma cells

ALDP（一种过氧化物酶体 ABC 蛋白）表达受损，导致人胶质母细胞瘤细胞脂质代谢紊乱

• 发表时间: 2006
• 作者: Morita M.;Mizuno S.;Tamura A.;and Imanaka T
• 通讯作者: and Imanaka T