Samyn Hannelore, Moerland Matthijs, van Gent Teus, van Haperen Rien, Grosveld Frank, van Tol Arie, de Crom Rini
Department of Cell Biology & Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Atherosclerosis. 2009 Jun;204(2):429-34. doi: 10.1016/j.atherosclerosis.2008.10.020. Epub 2008 Oct 30.
Phospholipid transfer protein (PLTP) is a multifunctional protein synthesized by various cell types and secreted into the plasma. Plasma PLTP is able to transfer phospholipids between lipoproteins and modulate HDL particles. Mice with overexpression of human PLTP have an increased ability to generate pre beta-HDL, reduced total HDL levels and an increased susceptibility to atherosclerosis. As the macrophage is a key component of the atherosclerotic lesion and an important site of PLTP expression, we investigated the role of systemic and peripheral PLTP in macrophage cholesterol efflux and reverse cholesterol transport (RCT) in vivo. We used an assay in which (3)H-labelled cholesterol-loaded macrophages were injected intraperitoneally into recipient mice, and radioactivity was quantified in plasma, liver and faeces. Firstly, wild type macrophages were injected into wild type, PLTP transgenic (PLTPtg) and apoAI transgenic (apoAItg) mice. While plasma (3)H-tracer levels in apoAItg mice were increased compared with wild type mice, they were reduced in PLTPtg mice. Moreover, overexpression of PLTP significantly decreased faecal (3)H-tracer levels compared with wild type and apoAItg mice. Secondly, wild type mice were injected with peritoneal macrophages derived from PLTPtg or wild type mice. No significant difference in the amount of (3)H-tracer in plasma, liver or faeces was found between the two groups of mice. Our findings demonstrate that macrophage cholesterol efflux and RCT to faeces is impaired in PLTP transgenic mice, and that elevation of macrophage-PLTP does not affect RCT, indicating that higher systemic PLTP levels may promote atherosclerosis development by decreasing the rate of macrophage RCT.
磷脂转运蛋白（PLTP）是一种由多种细胞类型合成并分泌到血浆中的多功能蛋白。血浆中的PLTP能够在脂蛋白之间转运磷脂并调节高密度脂蛋白（HDL）颗粒。人类PLTP过表达的小鼠生成前β-HDL的能力增强，总HDL水平降低，对动脉粥样硬化的易感性增加。由于巨噬细胞是动脉粥样硬化病变的关键组成部分以及PLTP表达的重要部位，我们研究了全身和外周PLTP在体内巨噬细胞胆固醇流出和逆向胆固醇转运（RCT）中的作用。我们采用了一种实验方法，将用（3）H标记的载有胆固醇的巨噬细胞腹腔注射到受体小鼠体内，并对血浆、肝脏和粪便中的放射性进行定量。首先，将野生型巨噬细胞注射到野生型、PLTP转基因（PLTPtg）和载脂蛋白AI转基因（apoAItg）小鼠体内。与野生型小鼠相比，apoAItg小鼠血浆中（3）H示踪剂水平升高，而PLTPtg小鼠血浆中（3）H示踪剂水平降低。此外，与野生型和apoAItg小鼠相比，PLTP过表达显著降低了粪便中（3）H示踪剂水平。其次，给野生型小鼠注射来自PLTPtg或野生型小鼠的腹腔巨噬细胞。两组小鼠血浆、肝脏或粪便中（3）H示踪剂的量没有显著差异。我们的研究结果表明，PLTP转基因小鼠中巨噬细胞胆固醇流出和向粪便的RCT受损，并且巨噬细胞PLTP升高不影响RCT，这表明较高的全身PLTP水平可能通过降低巨噬细胞RCT速率促进动脉粥样硬化的发展。
