SMALL DENSE LOW-DENSITY-LIPOPROTEIN HAS INCREASED AFFINITY FOR LDL RECEPTOR-INDEPENDENT CELL-SURFACE BINDING-SITES - A POTENTIAL MECHANISM FOR INCREASED ATHEROGENICITY

Small dense low density lipoprotein (LDL) particles have altered apoli poprotein (apo) B conformation and lowered affinity for the LDL recept or (J. Biol, Chem. 1994, 269: 511-519), Herein, we examine the interac tion of small dense LDL with cell LDL receptor-independent binding sit es. Compared to normal LDL, at low LDL cell media concentrations (<10 mu g/ml), small dense LDL had decreased specific binding to the LDL re ceptor on normal fibroblasts at 4 degrees C, but a 2-fold increased bi nding to LDL receptor-independent cell sites. At higher LDL concentrat ion (100 mu g/ml), LDL receptor-independent binding of small dense LDL was 4.5-fold that of normal LDL in normal fibroblasts, but greater (2 - to 14-fold) in LDL receptor-negative fibroblasts. In LDL receptor-ne gative fibroblasts at 37 degrees C, small dense LDL had higher (3-fold ) cell association than normal size LDL but no effective LDL degradati on. At high LDL concentrations (greater than or equal to 100 mu g/ml), LDL binding to normal or LDL receptor-negative fibroblasts was not af fected by several anti-apoB monoclonal antibodies or by cell pretreatm ent with proteases, chondroitinase, or neuraminidase. In contrast, pre treating normal and receptor-negative fibroblasts with heparinase and heparitinase decreased LDL cell binding by 35% and 50%, respectively. Similarly, preincubation of receptor-negative fibroblasts with sodium chlorate, an inhibitor of proteoglycan sulfation, decreased LDL bindin g by about 45%. We hypothesize that small dense LDL might be more athe rogenic than normal size LDL due to decreased hepatic clearance by the LDL receptor, and enhanced anchoring to LDL receptor-independent bind ing sites in extrahepatic tissues (e.g., the arterial wall), a process mediated, in part, by cell surface proteoglycans.