Essential role for the (hepatic) LDL receptor in macrophage apolipoprotein E-induced reduction in serum cholesterol levels and atherosclerosis.
Apolipoprotein E (apoE) is a high affinity ligand for several receptor systems in the liver, including the low-density lipoprotein (LDL) receptor, and non-LDL receptor sites, like the LDL receptor-related protein (LRP), the putative remnant receptor and/or proteoglycans. Although the liver is the major source of apoE synthesis, apoE is also produced by a wide variety of other cell types, including macrophages. In the present study, the role of the LDL receptor in the removal of lipoprotein remnants, enriched with macrophage-derived apoE from the circulation, was determined using the technique of bone marrow transplantation (BMT). Reconstitution of macrophage apoE production in apoE-deficient mice resulted in a serum apoE concentration of only 2% of the concentration in wild-type C57Bl/6 mice. This low level of apoE nevertheless reduced VLDL and LDL cholesterol 12-fold (P<0.001) and fourfold (P<0.001), respectively, thereby reducing serum cholesterol levels and the susceptibility to atherosclerosis. In contrast, reconstitution of macrophage apoE synthesis in mice lacking both apoE and the LDL receptor induced only a twofold (P<0.001) reduction in VLDL cholesterol and had no significant effect on atherosclerotic lesion development, although serum apoE levels were 93% of the concentration in normal C57Bl/6 mice. In conclusion, a functional (hepatic) LDL receptor is essential for the efficient removal of macrophage apoE-enriched lipoprotein remnants from the circulation and thus for normalization of serum cholesterol levels and protection against atherosclerotic lesion development in apoE-deficient mice.
Van Eck
M
M
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands. m.eck@lacdr.leidenuniv.nl
Van Dijk
K W
KW
Herijgers
N
N
Hofker
M H
MH
Groot
P H
PH
Van Berkel
T J
TJ
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001161:Arteriosclerosis / Q000473:pathology / Q000517:prevention & control*; D001853:Bone Marrow / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood*; D008099:Liver / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*
D001057:Apolipoproteins E; D011973:Receptors, LDL; D002784:Cholesterol