2005 Fiscal Year Final Research Report Summary
Functional interaction of peroxisomal ABC proteins and acyl-CoA sythesis in glial cells
| Project/Area Number |
16590044
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | University of Toyama (2005)
Toyama Medical and Pharmaceutical University (2004) |
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Principal Investigator |
MORITA Masashi University of Toyama, Pharmaceutical Science, Research assistant, 薬学部, 助手 (20191033)
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| Co-Investigator(Kenkyū-buntansha) |
IMANAKA Tsuneo University of Toyama, Pharmaceutical Science, Professor, 薬学部, 教授 (50119559)
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| Project Period (FY) |
2004 – 2005
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| Keywords | adrenoleukodystorophy / neurodegeneration / ABC protein / peroxisome / glial cells / flavonoid / acyl-CoA synthesis / very long chain fatty acid |
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| Research Abstract |
1.X-linked adrenoleukodystorophy (ALD) is a neurodegenerative disorder characterized by an abnormal accumulation of very long chain fatty acid (VLCFA). It is caused by a defect in the gene ABCD1 which encodes the peroxisomal membrane ABC protein, ALDP. However, the function of ALDP in CNS and the mechanism of the neurodegeneration in X-ALD were still unclear. In the present study, we have analyzed lipid metabolisms in ALDP-knockdown glioblastoma cells. In the ALDP-knockdown cells, the VLCFA β-oxidation activity was decreased by 〜70%. In addition, incorporation of [1-^<14>C]lignoceric acid into cholesterol ester fractions was increased in these cells. Furthermore, the incorporation of [2-^<14>C]acetic acid into cholesterol was significantly decreased and the cholesterol mass was increased in the ALDP-knockdown cells. These results indicate that in glial cells dysfunction of ALDP leads to the disruption of cholesterol metabolism as well as VLCFA metabolisms.
2.We analyzed the lipid metabolisms of primary microglia and astrocyte prepared from ALD-KO mouse. The VLCFA β-oxidation activity was significantly decreased when compared with that from wild mouse. These glial cells are reported to have important roles in neuronal functions. Disruption of VLCFA metabolisms in these cells could lead to the neurodegeneration in X-ALD.
3.We found that baicalein 5,6,7-trimethyl ether, a flavonoid derivative, have an ability to normalize the abnormal VLCFA metabolisms in X-ALD fibroblasts. This flavonoid derivative stimulated the peroxisomal VLCFA β-oxidation but inhibited the mitochondrial fatty acid β-oxidation. The flavonoid activated the acyl-CoA synthetase activities, suggesting that up-regulation of acyl-CoA synthetases could result in the stimulation of the VLCFA β-oxidation.
4.A novel medium-chain acyl-CoA synthetase was cloned and characterized. This enzyme was expressed in brain, adrenal gland, ovary and testis.
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Research Products
(14 results)
