Site-specific modification of apolipoprotein B by advanced glycosylation end-products: implications for lipoprotein clearance and atherogenesis.
An AGE-modified form of LDL (AGE-LDL) circulates in patients with diabetes mellitus or renal insufficiency and shows impaired plasma clearance kinetics when injected into transgenic mice that express the human LDL receptor. The advanced glycosylation inhibitor aminoguanidine decreases plasma LDL in diabetic patients, further suggesting that the AGE modification of LDL contributes significantly to increased LDL in vivo. We utilized AGE-specific antibodies to identify the major site(s) of AGE modification within apolipoprotein B (apoB), which impairs the binding of AGE-LDL by human fibroblast LDL receptors. Despite the large size of apoB (4536 amino acid residues) and its high content of potentially reactive lysines, the predominant site of AGE-immunoreactivity was found to lie within a single 67 amino acid domain located 1791 residues N-terminal to the LDL receptor binding site. These data point to the high specificity and reactivity of this site toward AGE formation and to a significant structural interaction between this region of apoB and the LDL receptor binding domain. A low but detectable degree of AGE modification was found to affect this site in LDL which was isolated from normal, non-diabetic individuals, suggesting that advanced glycosylation may contribute to elevated LDL in the general population as well.
Bucala
R
R
Picower Institute for Medical Research, New York, USA. rbucala@picower.edu
D000595:Amino Acid Sequence; D000818:Animals; D001055:Apolipoproteins B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism*; D001665:Binding Sites; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011973:Receptors, LDL / Q000378:metabolism
D001055:Apolipoproteins B; D017127:Glycation End Products, Advanced; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D011973:Receptors, LDL