出版社：American Society for Biochemistry and Molecular Biology
摘要：Factors that regulate apolipoprotein E (apoE) secretion by macrophageswill have important effects on vessel wall lipid flux and atherosclerosis.Macrophages express the LDL receptor, which binds apoE withhigh affinity and could thereby affect the net secretion ofapoE from macrophages. In these studies, we demonstrate thattreatment of J774 macrophages transfected to constitutivelyexpress a human apoE3 cDNA with simvastatin, to increase LDLreceptor activity, reduces the secretion of apoE. To furtherexamine the relationship between LDL receptor expression andapoE secretion from macrophages, mouse peritoneal macrophages(MPMs) were isolated from mice with constitutively high expressionof human LDL receptor to increase overall LDL receptor expressionby 2- to 3-fold. Cells with increased LDL receptor expressionalso showed reduced apoE secretion compared with MPMs with basalLDL receptor expression. The effect of changes in LDL receptorexpression on apoE secretion was isoform-specific, with greaterreduction of apoE4 compared with apoE3 secretion and no reductionof apoE2 secretion, paralleling the known affinity of each isoformfor LDL receptor binding. The effect of the LDL receptor onapoE secretion for each isoform was further reflected in LDLreceptor-dependent changes in apoE-mediated cholesterol efflux.These results establish a regulatory interaction between twobranches of macrophage sterol homeostatic pathways that couldfacilitate a rapid response to changes in macrophage sterolcontent relative to need.Supplementary key words atherosclerosis • apolipoproteins • lipoprotein receptors • low density lipoprotein • apolipoprotein E
Abbreviations: apoE, apolipoprotein E; Ldlr, macrophages with increased low density lipoprotein receptor expression; MPM, mouse peritoneal macrophage; WT, macrophages with basal low density lipoprotein expression
