Regulation of macrophage apoE secretion and sterol efflux by the LDL receptor

Danijela Lucic, Zhi Hua Huang, De Sheng Gu, Michael K. Altenburg, Nobuyo Maeda, and Theodore Mazzone

Medicine, University of Illinois Chicago, Chicago, IL

Corresponding Author: tmazzone{at}uic.edu

Factors that regulate apoE secretion by macrophages will have important effects on vessel wall lipid flux and atherosclerosis. Macrophages express the low density lipoprotein (LDL) receptor, which binds apoE with high affinity and could thereby impact 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, in order 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 (MPM) were isolated from mice with constitutively high expression of human LDL receptor to increase overall LDL receptor expression by 2-3 fold. Cells with increased LDL receptor expression also showed reduced apoE secretion compared to MPM 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 to apoE3, and no reduction of apoE2 secretion; paralleling the known affinity of each isoform for LDL receptor binding. The effect of 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 limbs of macrophage sterol homeostatic pathways that could facilitate a rapid response to changes in macrophage sterol content relative to need.

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