Department of Pharmacology, University of Colorado at Denver, Aurora, CO 80045, USA.
J Lipid Res. 2011 Nov;52(11):2070-83. doi: 10.1194/jlr.M019174. Epub 2011 Aug 31.
Although LDL is rendered proatherogenic by various experimental treatments (e.g., acetylation), the exact structural changes that drive LDL transformation in vivo remain enigmatic. Among the many hypothesized targets of oxidative modification are cholesterol esters (CE). This family of neutral lipids, which carries a highly unsaturated pool of fatty acyl groups, is the main component of both LDL particles and atherosclerotic plaques. Tandem mass spectrometry (MS/MS) was employed to reveal abundant and diverse oxidized CEs (oxCE), including novel oxidation products, within human peripheral vascular lesions. These oxCE species composed up to 40% of the total CE pool, with cholesteryl linoleate being oxidized to the greatest extent. Imaging mass spectrometry studies showed that oxCE was entirely confined within the plaque, along with unmodified CE and triacylglyceride (TAG). Interestingly, we found no evidence for TAG oxidation, although polyunsaturated species were abundant. Enzymatic oxidation of cholesteryl linoleate by 15-lipoxygenase (15-LO), an enzyme often invoked in CE oxidation, initially results in a regio- and stereospecific product. Analysis of intact cholesteryl hydroxyoctadecadienoate isomers in human atheromata revealed no regio- or stereospecificity, indicating 15-LO was either not a major source of oxCE or nonenzymatic processes had eroded any product specificity.
尽管 LDL 经各种实验处理（例如乙酰化）变得促动脉粥样硬化，但导致 LDL 在体内转化的确切结构变化仍然是个谜。在氧化修饰的众多假设靶点中，胆固醇酯（CE）备受关注。这类带高度不饱和脂肪酸酰基池的中性脂质，是 LDL 颗粒和动脉粥样硬化斑块的主要成分。串联质谱（MS/MS）用于揭示人外周血管病变中丰富多样的氧化 CE（oxCE），包括新型氧化产物。这些 oxCE 种类占总 CE 池的 40%，其中胆甾醇亚油酸氧化程度最高。成像质谱研究表明，oxCE 与未修饰的 CE 和三酰基甘油（TAG）完全局限于斑块内。有趣的是，尽管多不饱和物质丰富，但我们没有发现 TAG 氧化的证据。15-脂氧合酶（15-LO）是一种常被认为参与 CE 氧化的酶，它对胆甾醇亚油酸的酶促氧化最初会产生区域和立体特异性产物。对人动脉粥样硬化中完整的胆甾醇羟基十八碳二烯酸异构体的分析显示，不存在区域或立体特异性，这表明 15-LO 不是 oxCE 的主要来源，或者非酶过程侵蚀了任何产物特异性。
