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 apolipoprotein (apo) B conformation and lowered affinity for the LDL receptor (J. Biol. Chem. 1994. 269: 511-519). Herein, we examine the interaction of small dense LDL with cell LDL receptor-independent binding sites. Compared to normal LDL, at low LDL cell media concentrations (<10 microg/ml), small dense LDL had decreased specific binding to the LDL receptor on normal fibroblasts at 4 degrees C, but a 2-fold increased binding to LDL receptor-independent cell sites. At higher LDL concentration (100 microg/ 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-negative fibroblasts at 37 degrees C, small dense LDL had higher (3-fold) cell association than normal size LDL but no effective LDL degradation. At high LDL concentrations (> or =100 microg/ml), LDL binding to normal or LDL receptor-negative fibroblasts was not affected by several anti-apoB monoclonal antibodies or by cell pretreatment with proteases, chondroitinase, or neuraminidase. In contrast, pretreating 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 binding by about 45%. We hypothesize that small dense LDL might be more atherogenic than normal size LDL due to decreased hepatic clearance by the LDL receptor, and enhanced anchoring to LDL receptor-independent binding sites in extrahepatic tissues (e.g., the arterial wall), a process mediated, in part, by cell surface proteoglycans.
Galeano
N F
NF
Department of Pediatrics, Columbia University, New York, New York 10032, USA.
Al-Haideri
M
M
Keyserman
F
F
Rumsey
S C
SC
Deckelbaum
R J
RJ
D001055:Apolipoproteins B / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000032:analysis; D002788:Cholesterol Esters / Q000032:analysis; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D010743:Phospholipids / Q000032:analysis; D011487:Protein Conformation; D011973:Receptors, LDL / Q000378:metabolism; D012867:Skin / Q000378:metabolism*; D014280:Triglycerides / Q000032:analysis
D001055:Apolipoproteins B; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D010743:Phospholipids; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol