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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1501.)
© 2001 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

LR11, a Mosaic LDL Receptor Family Member, Mediates the Uptake of ApoE-Rich Lipoproteins In Vitro

Kouichi Taira; Hideaki Bujo; Satoshi Hirayama; Hiroyuki Yamazaki; Tatsuro Kanaki; Kazuo Takahashi; Itsuko Ishii; Takashi Miida; Wolfgang Johann Schneider; Yasushi Saito

From the Department of Clinical Cell Biology, F5 (K. Taira, S.H., T.K, K. Takahashi, Y.S.), the Department of Genome Research and Clinical Application, M6 (H.B.), Graduate School of Medicine, and the Laboratory of Clinical Pharmacology (I.I.), Faculty of Pharmaceutical Sciences, Chiba University, Chiba, Japan; Kowa Research Institute (H.Y.), Kowa Co Ltd, Tokyo, Japan; the Clinical Laboratory (T.M.), Niigata University School of Medicine, Niigata, Japan; and the Department of Molecular Genetics (S.H., W.J.S.), Biocenter and University of Vienna, Vienna, Austria.

Correspondence to Dr Hideaki Bujo, Department of Genome Research and Clinical Application, M6, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail hbujo{at}intmed02.m.chiba-u.ac.jp

Abstract—— 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, ß-very low density lipoproteins (VLDLs), with a high affinity similar to that of other members, such as the LDLR and VLDL receptor. RAP and ß-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 ß-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 ß-VLDL; these cells also show increased accumulation of cholesteryl esters when incubated with ß-VLDL. Incubation for 48 hours with ß-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.

Key Words: LDL receptors • atherosclerosis • smooth muscle cells • ß-VLDL

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