Metformin restores impaired HDL-mediated cholesterol efflux due to glycation.
High-density lipoprotein (HDL) mediates cholesterol efflux, which is the initial and rate-limiting step of reverse cholesterol transport. The present study was undertaken to evaluate the effect, on macrophage cholesterol efflux, of functional modification of HDL by its glycation. We also investigated the effects of the glycation-inhibitors metformin (MF) and aminoguanidine (AG) on glycated HDL-mediated cholesterol efflux. Human plasma HDL (5mg protein/mL) was glycated by incubation with 3-deoxyglucosone (3-DG). Glycation was monitored by measuring carboxymethyl-lysine (CML). HDL-mediated cholesterol efflux was determined using human THP-1-derived macrophages pre-labeled with [(3)H]-cholesterol. To measure expression of potential factors related to the efflux in the macrophages, ATP-binding cassette transporter (ABC) G1 was analyzed by real-time quantitative RT-PCR and Western blot. Glycation of HDL significantly reduced the HDL-mediated cholesterol efflux from THP-1-derived macrophages (87.7+/-4.2% of control, n=9, p<0.0001). In the presence of metformin or aminoguanidine (100mM), glycated HDL-mediated cholesterol efflux was restored to 97.5+/-4.3% and 96.9+/-3.1%, respectively. Exogenous HDL reduced ABCG1 mRNA and protein expression in THP-1-derived macrophages, but glycation deprived HDL of this effect. We conclude that glycated HDL particles are ineffective as acceptors of ABCG1-mediated cholesterol efflux; and this may explain, at least in part, accelerated atherosclerosis in diabetic patients. Metformin serves as a possible candidate to restore impaired cholesterol efflux and reverse cholesterol transport.
Matsuki
Kota
K
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
Tamasawa
Naoki
N
Yamashita
Maki
M
Tanabe
Jutaro
J
Murakami
Hiroshi
H
Matsui
Jun
J
Imaizumi
Tadaatsu
T
Satoh
Kei
K
Suda
Toshihiro
T
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D003847:Deoxyglucose / Q000031:analogs & derivatives / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors; D006031:Glycosylation; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*
C419353:ABCG1 protein, human; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D017127:Glycation End Products, Advanced; D006146:Guanidines; D008075:Lipoproteins, HDL; D008687:Metformin; D002784:Cholesterol; D003847:Deoxyglucose; C016350:3-deoxyglucosone; C004479:pimagedine