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Originally published In Press as doi:10.1074/jbc.M208786200 on February 21, 2003

J. Biol. Chem., Vol. 278, Issue 18, 15758-15764, May 2, 2003
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The Low Density Lipoprotein Receptor-related Protein Complexes with Cell Surface Heparan Sulfate Proteoglycans to Regulate Proteoglycan-mediated Lipoprotein Catabolism*

Larissa C. Wilsie and Robert A. OrlandoDagger

From the Department of Biochemistry and Molecular Biology, University of New Mexico, Health Sciences Center, Albuquerque, New Mexico 87131-0001

It has been proposed that clearance of cholesterol-enriched very low density lipoprotein (VLDL) particles occurs through a multistep process beginning with their initial binding to cell-surface heparan sulfate proteoglycans (HSPG), followed by their uptake into cells by a receptor-mediated process that utilizes members of the low density lipoprotein receptor (LDLR) family, including the low density lipoprotein receptor-related protein (LRP). We have further explored the relationship between HSPG binding of VLDL and its subsequent internalization by focusing on the LRP pathway using a cell line deficient in LDLR. In this study, we show that LRP and HSPG are part of a co-immunoprecipitable complex at the cell surface demonstrating a novel association for these two cell surface receptors. Cell surface binding assays show that this complex can be disrupted by an LRP-specific ligand binding antagonist, which in turn leads to increased VLDL binding and degradation. The increase in VLDL binding results from an increase in the availability of HSPG sites as treatment with heparinase or competitors of glycosaminoglycan chain addition eliminated the augmented binding. From these results we propose a model whereby LRP regulates the availability of VLDL binding sites at the cell surface by complexing with HSPG. Once HSPG dissociates from LRP, it is then able to bind and internalize VLDL independent of LRP endocytic activity. We conclude that HSPG and LRP together participate in VLDL clearance by means of a synergistic relationship.

* This work was supported by National Institutes of Health Grant HL63291 (to R. A. O.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: MSC08-4670, 1 University of New Mexico, Albuquerque, NM 87131. Tel.: 505-272-5593; Fax: 505-272-3518; E-mail: rorlando@salud.unm.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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