Pathophysiological role of lipid molecules produced by 12/l5-lipoxygenase

12/l5-脂氧合酶产生的脂质分子的病理生理作用

• 批准号: 12470024
• 负责人: YOSHIMOTO Tanihiro
• 金额: $ 9.09万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470024/
• 关键词: Lipoxygenase; Macrophage; Oxidized LDL; LDL receptor-related protein; Cholesterol ester; Translocation; 12; 15-リポキシゲナーゼ; 受容体; スカベンジャー受容体

Lipoxygenase incorporates a molecular oxygen regiospecifically and stereospeciflcally into unsaturated fatty acids. There are four classes of enzymes in mammalian tissues; 5-, 8-, 12-, and 15-lipoxygenases, named by the number indicating oxygenation site of arachidonic acid as a substrate. Among the enzymes, 12-lipoxygenases are widely distributed in various tissues and species, and there are three isoforms: platelet, leukocyte and epidermis types. Since the leukocyte 12-lipoxygenase and 15-lipoxygenase-1 are highly related in their primary structures and enzymological properties, these enzymes are collectively called as 12/15-lipoxygenase. A number of evidences support the role of 12/15-lipoxygenase in LDL oxidation. In order to investigate precise mechanisms of the 12/15-lipoxygenase-mediated LDL oxidation, we established a mouse macrophage-like J774A1 cell line overexpressing porcine leukocyte 12-lipoxygenase. The presence of regio- and stereospeciflcally oxygenated product of cholesteryl linoleate in the LDL indicates that the 12/15-lipoxygenase is responsible for cell-mediated LDL oxidation. We also showed that LDL receptor-related protein (LRP) was required for the enzyme-mediated LDL oxidation by macrophages. Furthermore, cholesterol ester selectively transferred from the LDL particle to the plasma membrane via LRP is oxygenated by 12/15-lipoxygenase translocated to this membrane:

脂氧合酶在不饱和脂肪酸中以区域特异性和立体特异性结合一个分子氧。哺乳动物组织中有四类酶：5-、8-、12-和15-脂氧合酶，以花生四烯酸为底物的氧化部位的数量命名。在这些酶中，12-脂氧合酶广泛分布于各种组织和物种中，有三种同工酶：血小板、白细胞和表皮。由于白细胞12-脂氧合酶和15-脂氧合酶-1在一级结构和酶学性质上高度相关，因此统称为12/15-脂氧合酶。许多证据支持12/15-脂氧合酶在低密度脂蛋白氧化中的作用。为了探讨12/15-脂氧合酶介导低密度脂蛋白氧化的确切机制，我们建立了高表达猪白细胞12-脂氧合酶的小鼠巨噬细胞样细胞系J774A1。在低密度脂蛋白中存在区域和立体特异性氧化产物，表明12/15-脂氧合酶负责细胞介导的低密度脂蛋白氧化。我们还发现，巨噬细胞的酶介导的低密度脂蛋白氧化需要低密度脂蛋白受体相关蛋白(LRP)。此外，通过LRP从低密度脂蛋白颗粒选择性地转移到质膜上的胆固醇酯被转移到膜上的12/15-脂氧合酶氧化：

项目成果

吉本谷博: "基礎生化学実験法(分担執筆)"東京化学同人(日本生化学会編). 338 (2000)

吉本谷浩：《基本生化实验方法（合着）》东京化学同人（日本生化会编）338（2000）。

Zhuang D.-M., Kawajiri H., Takahashi T. and Yoshimoto T.: "Suppression of prostaglandin E2-mediated c-fos mRNA induction by interleukin-4 in murine macrophages"J Biochem. 127. 451-456 (2000)

Zhuang D.-M.、Kawajiri H.、Takahashi T. 和 Yoshimoto T.：“小鼠巨噬细胞中白细胞介素 4 抑制前列腺素 E2 介导的 c-fos mRNA 诱导”J Biochem。

Kawajiri H., Zhuang D.-M., Qiao N., Yoshimoto T., Yamamoto M., Iseki S. and Hamaguchi K.: "Expression of arachidonate 12-lipoxygenase in rat tissues: Role of the enzyme in glucagon secretion"J Histochem Cytochem. 48. 1411-1420 (2000)

Kawajiri H.、Zhong D.-M.、Qiao N.、Yoshimoto T.、Yamamoto M.、Iseki S. 和 Hamaguchi K.：“大鼠组织中花生四烯酸 12-脂氧合酶的表达：该酶在胰高血糖素分泌中的作用”

Xu, W., et al.: "Low density lipoprotein receptor-related protein is required for macrophage-mediated oxidation of low density lipoprotein by 12/15-lipoxygenase"J. Biol. Chem.. 276. 36454-36549 (2001)

Xu, W., et al.：“低密度脂蛋白受体相关蛋白是巨噬细胞介导的 12/15-脂氧合酶氧化低密度脂蛋白所必需的”J.

Zhuang,D.-M. et al.: "Suppression of prostaglandin E_2-mediated c-fos mRNA induction by interleukin-4 in murine macrophages"J.Biochem.. 127. 451-456 (2000)

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