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- Title
Metformin Improves HDL-Mediated Cholesterol Efflux Through the Inhibition of HDL Glycation.
- Authors
Matsuki, Kota; Tamasawa, Naoki; Yamashita, Maki; Tanabe, Jutaro; Murakami, Hiroshi; Matsui, Jun; Suda, Toshihiro
- Abstract
[Study Aim] HDL makes an important athero-protective role in reverse cholesterol transport (RCT). We hypothesized that non-specific glycation would disturb the function of plasma lipoproteins in diabetes. We made glycated HDL and determined its ability of cholesterol efflux. [Method]1) Production of glycated HDL: Human HDL (CALBIOCHEM, 5mg/ml) was glycated under the incubation with 3-deoxyglucosone (3-DG, 0-100mM) in 37 degree for 3, 7 and 14 days. Glycated products were confirmed by measuring the concentration of carboxymethyl-lysine (CML). Finally, we determined the glycation condition as the incubation with 100 mM 3-DG for 7 days. 2) Comparison of glycated HDL-mediated of cholesterol efflux with non-glycated HDL: Human monocyte derived THP-1 cells were developed to macrophages and labeled with ³H-cholesterol (0.6µCi/ml). After the macrophage incubation adding glycated HDL (50 µg/ml) into the medium for 24 hours, the rate of labeled cholesterol pulled out from the macrophages was measured as cholesterol efflux. The result was compared with that of non-glycated HDL. 3) Effect of metformin for glycation of HDL and for HDL-mediated cholesterol efflux: We investigated the role of glycation-inhibitors; metformin and aminoguanidine(AGD) on HDL-mediated cholesterol efflux. THP-1 derived macrophages were glycated with 3-DG adding metformin or AGD (0-100 mM). Then, glycated HDL-mediated cholesterol efflux was determined and compared. [Result]1) It was confirmed that human HDL was glycated with 3-DG by dose and time dependently by measuring CIVIL (CML 2.361→3.845µg/ml). 2) Glycated HDL revealed significantly reduced cholesterol efflux compared with that of non-glycated HDL (-10.0±3.41%). 3) Under the existence of AGD (100mM), the glycated HDL-mediated efflux had significantly inhibited the reduction of the efflux from -10.0±3.41 to -3.45±3.20%. On the other hand, metformin (100mM) had improved the efflux to +1.60±2.52% and metformin was much more effective to glycated HDL-mediated cholesterol efflux than AGD. [Conclusion] We demonstrated the functional disorder in HDL particles suffering glycation in diabetes. Metformin is structurally related to aminoguanidine, the most extensively investigated inhibitor of advanced glycation end-products (AGEs) formation. We suggested the possibility that metoholmin improved the abnormal function of HDL by inhibition of HDL-glycation and other actions comparing with AGD.
- Subjects
HIGH density lipoproteins; BLOOD cholesterol; BIOLOGICAL transport; ENZYME inhibitors; DIABETES; MACROPHAGES
- Publication
Diabetes, 2007, Vol 56, pA152
- ISSN
0012-1797
- Publication type
Article