Nonenzymatic glycosylation of HDL resulting in inhibition of high-affinity binding to cultured human fibroblasts.
Nonenzymatic glycosylation of plasma proteins may contribute to the excess risk of developing atherosclerosis in patients with diabetes mellitus. Because high-density lipoprotein (HDL) is believed to protect against atherosclerosis and is glycosylated at increased levels in diabetic individuals, the effects of nonenzymatic glycosylation of HDL3 on binding of HDL3 to cultured fibroblasts and to the candidate HDL-receptor protein were examined. HDL3 was glycosylated in vitro with glucose alone or in combination with sodium cyanoborohydride. With this catalyst, up to 40-50% of the lysine residues could be glycosylated, resulting in a progressive drop to nearly 60% in high-affinity binding to cultured fibroblasts at 4 degrees C. Binding to the 110,000-Mr candidate HDL-receptor protein was reduced by almost 75%. At levels of HDL glycosylation equivalent to the 3-5% observed in diabetes, high-affinity binding to fibroblasts at 4 degrees C was diminished by up to 15-20%. Binding kinetic studies paradoxically suggested that glycosylated HDL3 binds with higher affinity to a reduced number of binding sites. The findings in this study suggest that nonenzymatically glycosylated HDL may be functionally abnormal and might contribute to the development of atherosclerosis in patients with diabetes mellitus.
Duell
P B
PB
Division of Metabolism, University of Washington, Seattle, Washington.
Oram
J F
JF
Bierman
E L
EL
D000818:Animals; D002352:Carrier Proteins; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006031:Glycosylation; D006801:Humans; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D018110:Receptors, Lipoprotein; D012016:Reference Values; D012867:Skin / Q000378:metabolism*; D013395:Sucrose / Q000494:pharmacology
D002352:Carrier Proteins; D008075:Lipoproteins, HDL; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface; D018110:Receptors, Lipoprotein; C031616:high density lipoprotein receptors; C075197:high density lipoprotein binding protein; D013395:Sucrose; D005947:Glucose