LR11, a mosaic LDL receptor family member, mediates the uptake of ApoE-rich lipoproteins in vitro.
Since the molecular identification of the low density lipoprotein receptor (LDLR), an ever increasing number of related proteins have been discovered. These receptors belonging to the LDLR family are thought to play key roles in lipoprotein metabolism in a variety of tissues, including the arterial wall. We have discovered that the expression of a 250-kDa mosaic LDLR-related protein, which we termed LR11 for the presence of 11 LDLR ligand-binding repeats, is markedly induced in smooth muscle cells in the hyperplastic intima of animal models used for the study of atherosclerosis. Here, we demonstrate that the human LR11, when overexpressed in hamster cells, binds and internalizes 39-kDa receptor-associated protein (RAP), an in vitro ligand for all receptors belonging to the LDLR family. Furthermore, LR11 binds the apolipoprotein E (apoE)-rich lipoproteins, beta-very low density lipoproteins (VLDLs), with a high affinity similar to that of other members, such as the LDLR and VLDL receptor. RAP and beta-VLDL compete with each other; however, other serum lipoproteins are not able to inhibit their binding. LR11 shows specific binding of apoE-enriched HDL prepared from human cerebrospinal fluid as well as of beta-VLDL, suggesting that the apoE content of lipoproteins is most likely important for mediating the high-affinity binding to the receptor. LR11-overexpressing cells are able to internalize and degrade the bound beta-VLDL; these cells also show increased accumulation of cholesteryl esters when incubated with beta-VLDL. Incubation for 48 hours with beta-VLDL of LR11-overexpressing cells, but not of control cells, promotes the appearance of numerous intracellular lipid droplets. Taken together, LR11, a mosaic LDLR family member whose expression in smooth muscle cells is markedly induced in atheroma, has all the properties of a receptor for the endocytosis of lipoproteins, particularly for the incorporation of apoE-rich lipoproteins.
Taira
K
K
Department of Clinical Cell Biology, Graduate School of Medicine, Faculty of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
Bujo
H
H
Hirayama
S
S
Yamazaki
H
H
Kanaki
T
T
Takahashi
K
K
Ishii
I
I
Miida
T
T
Schneider
W J
WJ
Saito
Y
Y
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D001161:Arteriosclerosis / Q000378:metabolism; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D004705:Endocytosis; D006023:Glycoproteins / Q000378:metabolism; D007150:Immunohistochemistry; D026563:LDL-Receptor Related Protein-Associated Protein; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D009154:Mutation; D011973:Receptors, LDL / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014162:Transfection
D001057:Apolipoproteins E; D002352:Carrier Proteins; D006023:Glycoproteins; D026563:LDL-Receptor Related Protein-Associated Protein; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D002784:Cholesterol