Nonenzymatic glycosylation of HDL and impaired HDL-receptor-mediated cholesterol efflux.
Previous studies have shown that nonenzymatic glycosylation of high-density lipoprotein (HDL) inhibits high-affinity binding to cultured cells and the candidate HDL-receptor protein. Because binding of HDL to its receptor is required for HDL-receptor-mediated cholesterol efflux from cells, we hypothesized that glycosylated HDL3 would have reduced ability to remove cholesterol from cells. HDL3 was glycosylated in vitro to achieve up to 40-50% reductions in free-lysine residues. Glycosylated HDL3 had a slightly greater ability than control HDL3 to sequester cholesterol directly from the plasma membrane, as predicted by changes in lipid composition. This process is independent of HDL-receptor binding and should not be influenced by reduced binding of HDL3. In contrast, efflux of intracellular cholesterol from cells, which is HDL-receptor dependent, was reduced 25-40%. The ability of glycosylated HDL3 to diminish cholesterol esterification was significantly reduced, indicating reduced net cholesterol efflux. Steady-state efflux of LDL-derived cholesterol was also markedly reduced. These findings suggest that nonenzymatically glycosylated HDL is functionally abnormal and might contribute to the accelerated development of atherosclerosis in patients with diabetes mellitus.
Duell
P B
PB
Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle.
Oram
J F
JF
Bierman
E L
EL
D002352:Carrier Proteins; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008563:Membrane Lipids / Q000378:metabolism; D008970:Molecular Weight; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface / Q000502:physiology*; D018110:Receptors, Lipoprotein; D012016:Reference Values; D012867:Skin / Q000378:metabolism*; D000093844:Glycated Proteins
D002352:Carrier Proteins; D002784:Cholesterol; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008563:Membrane Lipids; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface; D018110:Receptors, Lipoprotein; C051724:glycated lipoproteins, HDL; D000093844:Glycated Proteins; C031616:high density lipoprotein receptors; C075197:high density lipoprotein binding protein