2003 Fiscal Year Final Research Report Summary
Investigation of the functional molecules and mechanism on the LDL oxidation causing atherosclerosis -essential roles of 12/15-lipoxygenase-
| Project/Area Number |
14570101
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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 |
General medical chemistry
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| Research Institution | KANAZAWA UNIVERSITY |
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Principal Investigator |
TAKAHASHI Yoshitaka KANAZAWA UNIVERSITY, Graduate School of Medical Science, Lecturer, 大学院・医学系研究科, 講師 (10236333)
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| Co-Investigator(Kenkyū-buntansha) |
YOSHIMOTO Tanihiro KANAZAWA UNIVERSITY, Graduate School of Medical Science, Professor, 大学院・医学系研究科, 教授 (60127876)
MURAKAMI Takashi KANAZAWA UNIVERSITY, Graduate School of Medical Science, Assistant Professor, 大学院・医学系研究科, 助教授 (40210009)
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| Project Period (FY) |
2002 – 2003
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| Keywords | 12 / 15-Lipoxygenase / Macrophage / Oxidized LDL / LDL-receptor-related protein / Cholesteryl ester |
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| Research Abstract |
Oxidative modification of LDL is a critical step for the development of atherosclerosis. 12/15-Lipoxygenase highly expressed in macrophages is proposed to play a key role of the LDL oxidation ; however, the mechanism on the oxidation of extracellular LDL by intracellular enzyme was not known. We found that binding of LDL to the LDL-receptor-related protein(LRP), a cell-surface receptor expressed in macrophages, is required for the 12/15-lipoxygenase-mediates LDL oxidation by macrophages. The binding of the LDL to the LRP was found to translocates the cytosolic 12/15-lipoxygenase to the plasma membrane in macrophages and the transloation was required for the LDL oxidation. Furthermore, the cholesteryl ester in the LDL particle was selectively transferred to the plasma membrane of macrophages after binding of LRP. These results strongly suggest that cholesteryl ester in LDL is oxygenated in the plasma membrane by membrane-associated 12/15-lipoxygenase, transferred back to the LDL particle, and sequential radical chain reaction generates the oxidized LDL which is recognized by scavenger receptor in macrophages leading to the foam cell formation. These findings would be useful for the development of the medicines for this 'common disease with a novel mechanism.
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[Publications] Zhu, H., Y.Takahashi, W.Xu, H.Kawajiri, T.Murakami, M.Yamamoto, S.Iseki, T.Iwasaki, H.Hattori, T.Yoshimoto: "Low density lipoprotein receptor-related protein-mediated membrane translocation of 12/15-lipoxygenase is required for oxidation of low density lipoprotein by macrophages."J Biol Chem.. 278. 13350-13355 (2003)
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「研究成果報告書概要(欧文)」より
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