ApoE-mediated cholesterol efflux from macrophages: separation of autocrine and paracrine effects
ApoE-mediated cholesterol efflux from macrophages: separation of autocrine and paracrine effects
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DOI：
10.1152/ajpcell.00210.2004
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发表时间：
2005-03-01
影响因子：
5.5
通讯作者：
Fazio, S
中科院分区：
文献类型：
--
作者：
Dove, DE;Linton, MF;Fazio, S
血管壁中的巨噬细胞分泌高水平的载脂蛋白E（apoE）。胆固醇从巨噬细胞流出到apoE已被证明可以减少泡沫细胞形成并预防动脉粥样硬化。apoE分子可以介导胆固醇从最初分泌它的巨噬细胞（自分泌效应）或从周围巨噬细胞（旁分泌效应）流出。传统方法无法将这些系列效应分开。本文提出的新方法是通过使用一个简单的数学模型来解释稀释对载脂蛋白E介导的胆固醇流出的影响，从而分离自分泌和旁分泌效应。我们的结果表明，在非常稀的浓度，旁分泌的apoE的作用是不明显的，自分泌作用成为主要的介质外排。然而，在饱和浓度下，旁分泌apoE引起80 - 90%的apoE介导的胆固醇流出，而自分泌apoE则负责剩余的10 - 20%。这些结果表明，自分泌和旁分泌载脂蛋白E的相对重要性取决于局部分布体积的大小，在以前的载脂蛋白E功能的体外研究中没有考虑的因素。此外，apoE的自分泌作用在体内预防泡沫细胞形成中可能是关键的。这种新的方法可能适用于其他类型的混合自分泌/旁分泌系统，如信号转导系统。
Macrophages in the vessel wall secrete high levels of apolipoprotein E ( apoE). Cholesterol efflux from macrophages to apoE has been shown to decrease foam cell formation and prevent atherosclerosis. An apoE molecule can mediate cholesterol efflux from the macrophage that originally secreted it ( autocrine effect) or from surrounding macrophages ( paracrine effect). Traditional methodologies have not been able to separate these serial effects. The novel methodology presented here was developed to separate autocrine and paracrine effects by using a simple mathematical model to interpret the effects of dilution on apoE-mediated cholesterol efflux. Our results show that, at very dilute concentrations, the paracrine effect of apoE is not evident and the autocrine effect becomes the dominant mediator of efflux. However, at saturating concentrations, paracrine apoE causes 80 - 90% of the apoE-mediated cholesterol efflux, whereas autocrine apoE is responsible for the remaining 10 - 20%. These results suggest that the relative importance of autocrine and paracrine apoE depends on the size of the local distribution volume, a factor not considered in previous in vitro studies of apoE function. Furthermore, autocrine effects of apoE could be critical in the prevention of foam cell formation in vivo. This novel methodology may be applicable to other types of mixed autocrine/paracrine systems, such as signal transduction systems.