Eicosapentaenoic acid inhibits glucose-induced membrane cholesterol crystalline domain formation through a potent antioxidant mechanism
Eicosapentaenoic acid inhibits glucose-induced membrane cholesterol crystalline domain formation through a potent antioxidant mechanism
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DOI：
10.1016/j.bbamem.2014.10.016
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发表时间：
2015-02-01
影响因子：
3.4
通讯作者：
Jacob, Robert F.
中科院分区：
文献类型：
--
作者：
Mason, R. Preston;Jacob, Robert F.
在动脉粥样硬化形成过程中，脂质氧化导致内皮功能障碍、炎症和泡沫细胞形成。葡萄糖也有助于脂质氧化和促进膜结构组织的病理变化，包括胆固醇结晶域的发展。在本研究中，我们测试了二十碳五烯酸（EPA）（一种用于治疗极高甘油三酯（TG）水平的omega-3脂肪酸）和其他TG降低剂（非诺贝特、烟酸和吉非罗齐）对人低密度脂蛋白（LDL）以及在葡萄糖（200 mg/dL）存在下制备的膜脂囊泡中脂质氧化的比较作用。我们还研究了EPA与阿托伐他汀O-羟基（活性）代谢物（ATM）组合的抗氧化作用。葡萄糖诱导的膜结构组织的变化进行了测量，使用小角X-射线散射的方法，并与脂质过氧化氢（LOON）水平的变化。发现EPA以剂量依赖性方式（1.0-10.0 μ M）抑制LDL氧化，并且与其它TG降低剂不同，其它TG降低剂与单独的载体处理相比没有显著效果。在暴露于高血糖条件下的膜脂囊泡中观察到类似的效应。EPA的抗氧化活性，如在葡萄糖处理的囊泡中观察到的，在与ATM的组合中显著增强。葡萄糖处理产生高度有序的膜限制性胆固醇结晶结构域，其与LOOH水平增加相关。在这项研究中测试的药物中，只有EPA抑制葡萄糖诱导的胆固醇结构域形成。这些数据表明，EPA，在药理学水平，抑制高血糖症引起的膜脂质结构组织的变化，通过有效的抗氧化机制与其独特的，与膜双层的物理化学相互作用。(C)2014作者由Elsevier B. V.发布。这是CC BY NC ND许可证下的开放获取文章（http：//creativecommons.org/licenses/by-nc-nd/3.0/）。
Lipid oxidation leads to endothelial dysfunction, inflammation, and foam cell formation during atherogenesis. Glucose also contributes to lipid oxidation and promotes pathologic changes in membrane structural organization, including the development of cholesterol crystalline domains. In this study, we tested the comparative effects of eicosapentaenoic acid (EPA), an omega-3 fatty acid indicated for the treatment of very high triglyceride (TG) levels, and other TG-lowering agents (fenofibrate, niacin, and gemfibrozil) on lipid oxidation in human low-density lipoprotein (LDL) as well as membrane lipid vesicles prepared in the presence of glucose (200 mg/dL). We also examined the antioxidant effects of EPA in combination with atorvastatin o-hydroxy (active) metabolite (ATM). Glucose-induced changes in membrane structural organization were measured using small angle x-ray scattering approaches and correlated with changes in lipid hydroperoxide (LOON) levels. EPA was found to inhibit LDL oxidation in a dose-dependent manner (1.0-10.0 mu M) and was distinguished from the other TG-lowering agents, which had no significant effect as compared to vehicle treatment alone. Similar effects were observed in membrane lipid vesicles exposed to hyperglycemic conditions. The antioxidant activity of EPA, as observed in glucose-treated vesicles, was significantly enhanced in combination with ATM. Glucose treatment produced highly-ordered, membrane-restricted, cholesterol crystalline domains, which correlated with increased LOOH levels. Of the agents tested in this study, only EPA inhibited glucose-induced cholesterol domain formation. These data demonstrate that EPA, at pharmacologic levels, inhibits hyperglycemia-induced changes in membrane lipid structural organization through a potent antioxidant mechanism associated with its distinct, physicochemical interactions with the membrane bilayer. (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY NC ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).