IDENTIFICATION OF THE MAJOR SITE OF APOLIPOPROTEIN-B MODIFICATION BY ADVANCED GLYCOSYLATION END-PRODUCTS BLOCKING UPTAKE BY THE LOW-DENSITY-LIPOPROTEIN RECEPTOR

Advanced glycosylation end products (AGEs) arise from glucose-derived Amadori products and have been implicated in the pathogenesis of diabe tic vascular disease, We recently reported the presence of an AGE-modi fied form of low density lipoprotein (LDL) that circulates in high amo unts in patients with diabetes or renal insufficiency and that exhibit s impaired plasma clearance kinetics, We utilized AGE-specific antibod ies to identify the major sites of AGE modification within protease-di gested preparations of apolipoprotein B that impair the binding of the AGE-modified form of LDL by human fibroblast LDL receptors, The predo minant site of AGE immunoreactivity was found to lie within a single, 67-amino acid region located 1791 residues NH2-terminal of the putativ e LDL receptor binding domain, These data point to the high reactivity and specificity of this site for AGE formation and provide further ev idence for important structural interactions between the LDL receptor binding domain and remote regions of the apolipoprotein B polypeptide.