Low-density lipoprotein from apolipoprotein E-deficient mice induces macrophage lipid accumulation in a CD36 and scavenger receptor class A-dependent manner.
OBJECTIVE
To investigate the potential of circulating low-density lipoprotein (LDL), isolated from apolipoprotein E (apoE)-deficient mice (E-/-LDL) and from LDL receptor-deficient mice (Lr-/-LDL), to induce foam cell formation.


RESULTS
Binding studies using COS-7 cells overexpressing CD36, J774 cells, and mouse peritoneal macrophages (MPMs) unexpectedly showed for the first time that E-/-LDL, which is enriched in cholesterol, is a high-affinity ligand for CD36 and exhibited greater macrophage uptake than Lr-/-LDL or normal LDL. Minimal copper-mediated oxidization of Lr-/-LDL or C57LDL in vitro resulted in increased ligand internalization, although cell uptake of these oxidized LDLs was lower than that of E-/-LDL, even at oxidation levels similar to that found in E-/-LDL. Treatment of MPMs with E-/-LDL and Lr-/-LDL (to a 2- to 3-fold lesser extent), but not normal LDL, resulted in significant cellular cholesteryl ester accumulation and foam cell formation. Experiments using MPMs lacking CD36, scavenger receptor class A (SR-A), or both, indicated a major contribution of CD36 ( approximately 50%), and to a lesser extent, SR-A (24% to 30%), to E-/-LDL uptake.


CONCLUSIONS
Because of its increased state of oxidation and high cholesterol content, LDL in apoE-deficient mice acts in a proatherogenic manner, without requiring further modification in the vascular wall, to induce foam cell formation through its uptake by scavenger receptors.
Zhao
Zhenze
Z
Department of Internal Medicine and Graduate Center for Nutritional Sciences, University of Kentucky Medical Center, Lexington, KY 40536, USA.
de Beer
Maria C
MC
Cai
Lei
L
Asmis
Reto
R
de Beer
Frederick C
FC
de Villiers
Willem J S
WJ
van der Westhuyzen
Deneys R
DR
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency*; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells / Q000737:chemistry / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D002522:Chlorocebus aethiops; D002788:Cholesterol Esters / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism; D018014:Gene Transfer Techniques; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011971:Receptors, Immunologic / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D014161:Transduction, Genetic / Q000379:methods
D001053:Apolipoproteins; D001057:Apolipoproteins E; D018955:CD36 Antigens; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; C099252:oxidized low density lipoprotein