Advanced glycation end product precursors impair ABCA1-dependent cholesterol removal from cells.
Abnormal HDL metabolism may contribute to the increased atherosclerosis associated with diabetes. The ATP-binding cassette transporter A1 (ABCA1) is an atheroprotective cell protein that mediates cholesterol transport from cells to apolipoprotein (apo) A-I, the major protein in HDL. Because formation of advanced glycation end products (AGEs) is associated with diabetic vascular complications, we examined the effects of carbonyls implicated in AGE formation on the ABCA1 pathway in cultured fibroblasts and macrophages. Treating cells with glycolaldehyde (GA) and glyoxal (GO) strongly inhibited ABCA1-dependent transport of cholesterol from cells to apoA-I, while methylglyoxal had little effect. This occurred under conditions where other lipoprotein receptors or lipid metabolic pathways were little affected, indicating that ABCA1 was uniquely sensitive to these carbonyls. GA and GO destabilized ABCA1 and nearly abolished its binding of apoA-I, indicating that these carbonyls directly modified ABCA1. Immunohistology of coronary arteries from hyperlipidemic swine revealed that inducing diabetes with streptozotocin increased atherosclerotic lesion area and dramatically reduced the fraction of macrophages that expressed detectable ABCA1. These results raise the possibility that reactive carbonyl-mediated damage to ABCA1 promotes accumulation of cholesterol in arterial macrophages and thus contribute to the increased cardiovascular disease associated with diabetes, insulin resistance, and other inflammatory conditions.
Department of Medicine, Box 356426, University of Washington, Seattle, WA 98195-6426, USA.
Marisa
M
Passarelli
Chongren
C
Tang
Thomas O
TO
McDonald
Kevin D
KD
O'Brien
Ross G
RG
Gerrity
Jay W
JW
Heinecke
John F
JF
Oram
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006037:Glyoxal / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008760:Methylguanidine / Q000494:pharmacology; D051379:Mice; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D006037:Glyoxal; D008760:Methylguanidine; D002784:Cholesterol; D000079:Acetaldehyde; C010972:glycolaldehyde