Identification of megalin/gp330 as a receptor for lipoprotein(a) in vitro

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Item Type:	Article
Title:	Identification of megalin/gp330 as a receptor for lipoprotein(a) in vitro
Creators Name:	Niemeier, A., Willnow, T.E., Dieplinger, H., Jacobsen, C., Meyer, N., Hilpert, J. and Beisiegel, U.
Abstract:	Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein of unknown physiological function. The mechanism of Lp(a) atherogenicity as well as its catabolic pathways are only incompletely understood at present. In this report, we show that the low density lipoprotein receptor (LDLR) gene family member megalin/glycoprotein (gp) 330 is capable of binding and mediating the cellular uptake and degradation of Lp(a) in vitro. A mouse embryonic yolk sac cell line with native expression of megalin/gp330 but genetically deficient in LDLR-related protein (LRP) and a control cell line carrying a double knockout for both LRP and megalin/gp330 were compared with regard to their ability to bind, internalize, and degrade dioctadecyltetramethylindocarbocyanine perchlorate (DiI)-fluorescence-labeled Lp(a) as well as equimolar amounts of 125I-labeled Lp(a) and LDL. Uptake and degradation of radiolabeled Lp(a) by the megalin/gp330-expressing cells were, on average, 2-fold higher than that of control cells. This difference could be completely abolished by addition of the receptor-associated protein, an inhibitor of ligand binding to megalin/gp330. Mutual suppression of the uptake of 125I-Lp(a) and of 125I-LDL by both unlabeled Lp(a) and LDL suggested that Lp(a) uptake is mediated at least partially by apolipoprotein B100. Binding and uptake of DiI-Lp(a) resulted in strong signals on megalin/gp330-expressing cells versus background only on control cells. In addition, we show that purified megalin/gp330, immobilized on a sensor chip, directly binds Lp(a) in a Ca2+-dependent manner with an affinity similar to that for LDL. We conclude that megalin/gp330 binds Lp(a) in vitro and is capable of mediating its cellular uptake and degradation.
Keywords:	Megalin, Glycoprotein 330, Lipoprotein(a), LDL, LDLR Gene Family, Animals, Mice
Source:	Arteriosclerosis Thrombosis and Vascular Biology
ISSN:	1079-5642
Publisher:	American Heart Association
Volume:	19
Number:	3
Page Range:	552-561
Date:	March 1999
Official Publication:	https://doi.org/10.1161/01.ATV.19.3.552
PubMed:	View item in PubMed

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