title: Apolipoprotein A-I glycation by glucose and reactive aldehydes alters phospholipid affinity but not cholesterol export from lipid-laden macrophages.
abstract: 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.
authors.affiliation: The Heart Research Institute, Sydney, New South Wales, Australia.
authors.forename: Bronwyn E
authors.initials: BE
authors.lastname: Brown
authors.forename: Estelle
authors.initials: E
authors.lastname: Nobecourt
authors.forename: Jingmin
authors.initials: J
authors.lastname: Zeng
authors.forename: Alicia J
authors.initials: AJ
authors.lastname: Jenkins
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Davies
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000328:Adult; D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism*; D001692:Biological Transport; D016022:Case-Control Studies; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D010743:Phospholipids / Q000378:metabolism*; D055815:Young Adult
chemical_list: D018528:ATP-Binding Cassette Transporters; D000447:Aldehydes; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D010743:Phospholipids; D002784:Cholesterol; D005947:Glucose