HEPARAN-SULFATE PROTEOGLYCAN-MEDIATED UPTAKE OF APOLIPOPROTEIN E-TRIGLYCERIDE-RICH LIPOPROTEIN PARTICLES - A MAJOR PATHWAY AT PHYSIOLOGICALPARTICLE CONCENTRATIONS

We explored potential mechanisms of non-low-density lipoprotein (LDL) receptor-mediated uptake of triglyceride-rich particles (TGRP) in the presence of apolipoprotein E (apo E). Human fibroblasts were incubated with model intermediate-density lipoprotein-(IDL-) sized TGRP (10-100 0 mu g of neutral lipid/mL) containing apo E. The extent of receptor-m ediated uptake of TGRP was assessed with (a) an anti-apo E monoclonal antibody, which blocks receptor interaction; (b) incubation with hepar in; (c) normal vs LDL receptor-negative fibroblasts; and (d) receptor- associated protein (RAP) to determine the potential contribution of LD L receptor-related protein (LRP). Cell surface heparan sulfate proteog lycan-(HSPG-) mediated uptake was examined with or without the additio n of heparinase and heparitinase to cell incubation mixtures. At low p article concentrations (less than or equal to 100 mu g of neutral lipi d/mL), almost all apo E-TGRP uptake was via the LDL receptor. At highe r particle concentrations, within the physiologic range (>250 mu g of neutral lipid/mL), most (greater than or equal to 60%) particle uptake and internalization was via HSPG-mediated pathways. This HSPG pathway did not involve classical lipoprotein receptors, such as LRP or the L DL receptor. These data suggest that in peripheral tissues, such as th e arterial wall, apo E may act in TGRP as a ligand for uptake not only via the LDL receptor and LRP pathways but also via HSPG pathways that are receptor independent. Thus, at physiologic particle concentration s apo E-TGRP can be bound and internalized in certain cells by relativ ely low affinity but high capacity HSPG-mediated pathways.