Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, USA.
Circ Res. 2012 Sep 28;111(8):1054-64. doi: 10.1161/CIRCRESAHA.112.270314. Epub 2012 Aug 8.
A high-fat diet accompanied by hypertriglyceridemia increases an individual's risk for development of atherosclerosis. An early event in this process is monocyte recruitment through binding to vascular cell adhesion molecule 1 (VCAM-1) upregulated on inflamed arterial endothelium. Diets high in polyunsaturated fatty acids (PUFAs) may provide athero-protection by ameliorating this effect.
We investigated the acute regulation of VCAM-1 expression in human aortic endothelial cells (HAEC) in response to triglyceride-rich lipoproteins (TGRL) isolated from subjects after consumption of a high-fat meal.
Postprandial TGRL isolated from 38 subjects were categorized as proatherogenic or antiatherogenic according to their capacity to alter the inflammatory response of HAEC. Proatherogenic TGRL increased expression of VCAM-1, intercellular adhesion molecule 1 (ICAM-1), and E-selectin by ≈20% compared with stimulation with tumor necrosis factor-α alone, whereas antiatherogenic TGRL decreased VCAM-1 expression by ≈20% while still upregulating ICAM-1. The relative atherogenicity of TGRL positively correlated with particle density of TG, apolipoprotein (Apo)CIII, ApoE, and cholesterol. Ω3-PUFA mimicked the effect of antiatherogenic TGRL by downregulating VCAM-1 expression. TGRL exerted this differential regulation of VCAM-1 by reciprocally modulating expression and activity of the transcription factor interferon regulatory factor 1 (IRF-1) and expression of microRNA 126 (miR-126). Overexpression or silencing of IRF-1 or miR-126 expression recapitulated the proatherogenic or antiatherogenic regulation of VCAM-1.
In response to a high-fat meal, TGRL bias the inflammatory response of endothelium via transcriptional and posttranscriptional editing of VCAM-1. Subjects with an anti-inflammatory response to a meal produced TGRL that was enriched in nonesterified fatty acids, decreased IRF-1 expression, increased miR-126 activity, and diminished monocyte arrest.
高脂饮食伴高甘油三酯血症会增加个体发生动脉粥样硬化的风险。该过程的早期事件是单核细胞通过与炎症动脉内皮上调的血管细胞粘附分子 1（VCAM-1）结合而募集。富含多不饱和脂肪酸（PUFA）的饮食可能通过改善这种作用来提供动脉保护。
我们研究了富含甘油三酯的脂蛋白（TGRL）在人主动脉内皮细胞（HAEC）中的 VCAM-1 表达的急性调节，这些 TGRL 是从接受高脂肪餐后的受试者中分离出来的。
根据其改变 HAEC 炎症反应的能力，将从 38 名受试者中分离出的餐后 TGRL 分为促动脉粥样硬化或抗动脉粥样硬化。与单独用肿瘤坏死因子-α刺激相比，促动脉粥样硬化 TGRL 使 VCAM-1、细胞间粘附分子 1（ICAM-1）和 E-选择素的表达增加了约 20%，而抗动脉粥样硬化 TGRL 使 VCAM-1 的表达减少了约 20%，同时仍上调了 ICAM-1。TGRL 的相对动脉粥样硬化性与 TG、载脂蛋白（Apo）CIII、ApoE 和胆固醇的颗粒密度呈正相关。ω3-PUFA 通过下调 VCAM-1 的表达来模拟抗动脉粥样硬化 TGRL 的作用。TGRL 通过反向调节转录因子干扰素调节因子 1（IRF-1）的表达和活性以及 microRNA 126（miR-126）的表达来发挥这种对 VCAM-1 的差异调节作用。IRF-1 或 miR-126 表达的过表达或沉默再现了 VCAM-1 的促动脉粥样硬化或抗动脉粥样硬化调节。
在高脂肪餐的刺激下，TGRL 通过 VCAM-1 的转录和转录后编辑来偏倚内皮的炎症反应。对膳食有抗炎反应的受试者产生的富含非酯化脂肪酸的 TGRL，降低了 IRF-1 的表达，增加了 miR-126 的活性，并减少了单核细胞的捕获。
