Apolipoprotein A-I glycation by glucose and reactive aldehydes alters phospholipid affinity but not cholesterol export from lipid-laden macrophages

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Bronwyn E Brown, Estelle Nobecourt, Jingmin Zeng, Alicia J Jenkins, Kerry-Anne Rye, Michael Jonathan Davies

Increased protein glycation in people with diabetes may promote atherosclerosis. This study examined the effects of non-enzymatic glycation on the association of lipid-free apolipoproteinA-I (apoA-I) with phospholipid, and cholesterol efflux from lipid-loaded macrophages to lipid-free and lipid-associated apoA-I. Glycation of lipid-free apoA-I by methylglyoxal and glycolaldehyde resulted in Arg, Lys and Trp loss, advanced glycation end-product formation and protein cross-linking. The association of apoA-I glycated by glucose, methylglyoxal or glycolaldehyde with phospholipid multilamellar vesicles was impaired in a glycating agent dose-dependent manner, with exposure of apoA-I to both 30 mM glucose (42% decrease in kslow) and 3 mM glycolaldehyde (50% decrease in kfast, 60% decrease in kslow) resulting is significantly reduced affinity. Cholesterol efflux to control or glycated lipid-free apoA-I, or discoidal reconstituted HDL containing glycated apoA-I (drHDL), was examined using cholesterol-loaded murine (J774A.1) macrophages treated to increase expression of ATP binding cassette transporters A1 (ABCA1) or G1 (ABCG1). Cholesterol efflux from J774A.1 macrophages to glycated lipid-free apoA-I via ABCA1 or glycated drHDL via an ABCG1-dependent mechanism was unaltered, as was efflux to minimally modified apoA-I from people with Type 1 diabetes, or controls. Changes to protein structure and function were prevented by the reactive carbonyl scavenger aminoguanidine. Overall these studies demonstrate that glycation of lipid-free apoA-I, particularly late glycation, modifies its structure, its capacity to bind phospholipids and but not ABCA1- or ABCG1-dependent cholesterol efflux from macrophages.

Original languageEnglish
JournalPLOS ONE
Volume8
Issue number5
Pages (from-to)e65430
ISSN1932-6203
DOIs
Publication statusPublished - 2013
Externally publishedYes

    Research areas

  • ATP-Binding Cassette Transporters, Adult, Aldehydes, Animals, Apolipoprotein A-I, Biological Transport, Case-Control Studies, Cell Line, Cholesterol, Diabetes Mellitus, Type 1, Female, Glucose, Glycosylation, Humans, Lipid Metabolism, Lipoproteins, HDL, Macrophages, Male, Mice, Phospholipids, Young Adult

ID: 128974281