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