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-relat ed protein, which we termed LR11 for the presence of 11 LDLR ligand-binding repeats, is markedly induced in smooth muscle cells in the hyperplastic in tima of animal models used for the study of atherosclerosis. Here, we demon strate that the human LR11, when overexpressed in hamster cells, binds and internalizes 39-kDa receptor-associated protein (RAP), an in vitro ligand f or all receptors belonging to the LDLR family. Furthermore, LR11 binds the apolipoprotein E (apoE)-rich lipoproteins, beta -very low density lipoprote ins (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; ho wever, other serum lipoproteins are not able to inhibit their binding. LR11 shows specific binding of apoE-enriched HDL prepared from human cerebrospi nal fluid as well as of beta -VLDL, suggesting that the apoE content of lip oproteins is most likely important for mediating the high-affinity binding to the receptor. LR11-overexpressing cells are able to internalize and degr ade the bound beta -VLDL; these cells also show increased accumulation of c holesterol esters when incubated with beta -VLDL. Incubation for 48 hours w ith beta -VLDL of LR11-overexpressing cells, but not of control cells, prom otes the appearance of numerous intracellular lipid droplets. Taken togethe r, LR11, a mosaic LDLR family member whose expression in smooth muscle cell s is markedly induced in atheroma, has all the properties of a receptor for the endocytosis of lipoproteins, particularly for the incorporation of apo E-rich lipoproteins.