The Low Density Lipoprotein Receptor-related Protein Complexes with Cell Surface Heparan Sulfate Proteoglycans to Regulate Proteoglycan-mediated Lipoprotein Catabolism

Abstract

It has been proposed that clearance of cholesterolenriched 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. Remnant lipoproteins originating from lipolytic processing of dietary chylomicrons and very low density lipoproteins (VLDL)1 synthesized by the liver are primary carriers in lipid transport and facilitate the delivery of cholesterol and triglycerides to hepatic and extrahepatic tissues. VLDL particles consist of apolipoprotein B (apoB) and apolipoproteins CI, CII, and CIII (1) with esterified cholesterol and triglycerides at their core, and an outer association of apolipoprotein E (apoE). Apo-CII is thought to activate lipoprotein lipase, necessary for lipolytic processing (2-4). ApoB (5, 6) and apoE (7,8) are required for receptor-mediated clearance of VLDL particles.Receptor-mediated clearance of circulating VLDL is a rapid and critical step for maintenance of proper plasma lipid levels. The half-life of injected VLDL is reported to be ϳ20 min in mice and rabbits (9). Elevated VLDL levels, as seen in type III hyperlipoproteinemia (10, 11), lead to elevated plasma triglyceride levels making VLDL highly atherogenic (5). Moreover, excessive VLDL uptake by macrophages results in cholesterol accumulation and foam cell formation (12, 13) increasing the risk for coronary heart disease and stroke.Clearance of VLDL is thought to occur through a multistep process. VLDL initially binds to cell surfaces through interactions with heparan sulfate proteoglycans (HSPG) (14), and this binding is mediated by apoE, which contains a high affinity heparan sulfate binding site (15, 16). Accordingly, apoE knockout mice...

A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

“…# P < 0.05; n = 4/group. sLRP-α to Schwann cells, consistent with the reported association of membrane-anchored LRP1 with heparin sulfate proteoglycans (64). However, the inhibition observed with heparin was incomplete.…”

LRP1 mediates the Shh-induced endocytosis of the GPC3-Shh complex

“…These proteins first bind with low affinity to the glycosaminoglycan (GAG) chains of cell surface HSPGs, and then they are 'presented' to LRP1 which mediates their internalization (Kanekiyo et al, 2011;Nykjaer and Willnow, 2002;Sarafanov et al, 2011;Wilsie and Orlando, 2003). In other words, the HSPGs act like docking sites that facilitate the interaction of the ligands with the endocytic receptors.…”

LRP1 controls biosynthetic and endocytic trafficking of neuronal prion protein

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