Heparan Sulfate Proteoglycan-Mediated Uptake of Apolipoprotein E−Triglyceride-Rich Lipoprotein Particles: A Major Pathway at Physiological Particle 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 (10−1000 μg of neutral lipid/mL) containing apo E. The extent of receptor-mediated uptake of TGRP was assessed with (a) an anti-apo E monoclonal antibody, which blocks receptor interaction; (b) incubation with heparin; (c) normal vs LDL receptor-negative fibroblasts; and (d) receptor-associated protein (RAP) to determine the potential contribution of LDL receptor-related protein (LRP). Cell surface heparan sulfate proteoglycan- (HSPG-) mediated uptake was examined with or without the addition of heparinase and heparitinase to cell incubation mixtures. At low particle concentrations (≤100 μg of neutral lipid/mL), almost all apo E−TGRP uptake was via the LDL receptor. At higher particle concentrations, within the physiologic range (>250 μ...