Lucic Danijela, Huang Zhi Hua, Gu De Sheng, Altenburg Michael K, Maeda Nobuyo, Mazzone Theodore
Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
J Lipid Res. 2007 Feb;48(2):366-72. doi: 10.1194/jlr.M600259-JLR200. Epub 2006 Nov 1.
Factors that regulate apolipoprotein E (apoE) secretion by macrophages will have important effects on vessel wall lipid flux and atherosclerosis. Macrophages express the LDL receptor, which binds apoE with high affinity and could thereby affect the net secretion of apoE from macrophages. In these studies, we demonstrate that treatment of J774 macrophages transfected to constitutively express a human apoE3 cDNA with simvastatin, to increase LDL receptor activity, reduces the secretion of apoE. To further examine the relationship between LDL receptor expression and apoE secretion from macrophages, mouse peritoneal macrophages (MPMs) were isolated from mice with constitutively high expression of human LDL receptor to increase overall LDL receptor expression by 2- to 3-fold. Cells with increased LDL receptor expression also showed reduced apoE secretion compared with MPMs with basal LDL receptor expression. The effect of changes in LDL receptor expression on apoE secretion was isoform-specific, with greater reduction of apoE4 compared with apoE3 secretion and no reduction of apoE2 secretion, paralleling the known affinity of each isoform for LDL receptor binding. The effect of the LDL receptor on apoE secretion for each isoform was further reflected in LDL receptor-dependent changes in apoE-mediated cholesterol efflux. These results establish a regulatory interaction between two branches of macrophage sterol homeostatic pathways that could facilitate a rapid response to changes in macrophage sterol content relative to need.
调节巨噬细胞载脂蛋白E（apoE）分泌的因素将对血管壁脂质通量和动脉粥样硬化产生重要影响。巨噬细胞表达低密度脂蛋白（LDL）受体，该受体与apoE具有高亲和力结合，从而可能影响巨噬细胞中apoE的净分泌。在这些研究中，我们证明，用辛伐他汀处理组成性表达人apoE3 cDNA的J774巨噬细胞以增加LDL受体活性，可降低apoE的分泌。为了进一步研究LDL受体表达与巨噬细胞apoE分泌之间的关系，从小鼠中分离出组成性高表达人LDL受体的小鼠腹膜巨噬细胞（MPM），以使总体LDL受体表达增加2至3倍。与具有基础LDL受体表达的MPM相比，LDL受体表达增加的细胞也显示出apoE分泌减少。LDL受体表达变化对apoE分泌的影响具有异构体特异性，与apoE3分泌相比，apoE4的减少更大，而apoE2分泌没有减少，这与每种异构体对LDL受体结合的已知亲和力平行。LDL受体对每种异构体apoE分泌的影响进一步反映在apoE介导的胆固醇流出的LDL受体依赖性变化中。这些结果建立了巨噬细胞固醇稳态途径两个分支之间的调节相互作用，这可能有助于对巨噬细胞固醇含量相对于需求的变化做出快速反应。
