Taira K, Bujo H, Hirayama S, Yamazaki H, Kanaki T, Takahashi K, Ishii I, Miida T, Schneider W J, Saito Y
Department of Clinical Cell Biology, Graduate School of Medicine, Faculty of Pharmaceutical Sciences, Chiba University, Chiba, Japan.
Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1501-6. doi: 10.1161/hq0901.094500.
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.
自从低密度脂蛋白受体（LDLR）的分子鉴定以来，已发现越来越多的相关蛋白。这些属于LDLR家族的受体被认为在包括动脉壁在内的多种组织的脂蛋白代谢中起关键作用。我们发现，一种250 kDa的镶嵌型LDLR相关蛋白（由于存在11个LDLR配体结合重复序列，我们将其命名为LR11）在用于动脉粥样硬化研究的动物模型增生内膜的平滑肌细胞中显著诱导表达。在此，我们证明，人LR11在仓鼠细胞中过表达时，能结合并内化39 kDa的受体相关蛋白（RAP），RAP是所有属于LDLR家族受体的体外配体。此外，LR11以与其他成员（如LDLR和极低密度脂蛋白受体）相似的高亲和力结合富含载脂蛋白E（apoE）的脂蛋白——β-极低密度脂蛋白（β-VLDL）。RAP和β-VLDL相互竞争；然而，其他血清脂蛋白不能抑制它们的结合。LR11显示出对从人脑脊液中制备的富含apoE的高密度脂蛋白（HDL）以及β-VLDL的特异性结合，这表明脂蛋白中的apoE含量很可能对介导与受体的高亲和力结合很重要。过表达LR11的细胞能够内化并降解结合的β-VLDL；这些细胞在与β-VLDL孵育时，胆固醇酯的积累也会增加。用β-VLDL孵育过表达LR11的细胞48小时，而非对照细胞，会促使大量细胞内脂滴出现。综上所述，LR11是一种镶嵌型LDLR家族成员，其在平滑肌细胞中的表达在动脉粥样瘤中显著诱导，具有脂蛋白内吞作用受体的所有特性，特别是对于富含apoE的脂蛋白的摄取。
