Reduced Expression of ATP-Binding Cassette Transporter G1 Increases Cholesterol Accumulation in Macrophages of Patients With Type 2 Diabetes Mellitus

• Published in: Circulation (New York, N.Y.) N.Y.), 2008-05, Vol.117 (21), p.2785-2792
• Main Authors: MAULDIN, Jeremy P, NAGELIN, Melissa H, WOJCIK, Allison J, SRINIVASAN, Suseela, SKAFLEN, Marcus D, AYERS, Carlos R, MCNAMARA, Coleen A, HEDRICK, Catherine C
• Format: Article
• Language: English
• Subjects: Associated diseases and complications; Atherosclerosis - metabolism; Atherosclerosis - physiopathology; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Differentiation - immunology; Cells, Cultured; Cholesterol Esters - metabolism; Cholesterol, HDL - metabolism; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Diabetic Angiopathies - metabolism; Diabetic Angiopathies - physiopathology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Gene Expression; Humans; Hydrocarbons, Fluorinated - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Male; Medical sciences; Middle Aged; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; Sulfonamides - pharmacology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.107.741314

Patients with type 2 diabetes mellitus are at increased risk for the development of atherosclerosis. A pivotal event in the development of atherosclerosis is macrophage foam cell formation. The ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 regulate macrophage cholesterol efflux and hence play a vital role in macrophage foam cell formation. We have previously found that chronic elevated glucose reduces ABCG1 expression. In the present study, we examined whether patients with type 2 diabetes mellitus had decreased ABCG1 and/or ABCA1, impaired cholesterol efflux, and increased macrophage foam cell formation. Blood was collected from patients with and without type 2 diabetes mellitus. Peripheral blood monocytes were differentiated into macrophages, and cholesterol efflux assays, immunoblots, histological analysis, and intracellular cholesteryl ester measurements were performed. Macrophages from patients with type 2 diabetes mellitus had a 30% reduction in cholesterol efflux with a corresponding 60% increase in cholesterol accumulation relative to control subjects. ABCG1 was present in macrophages from control subjects but was undetectable in macrophages from patients with type 2 diabetes mellitus. In contrast, ABCA1 expression in macrophages was similar in both control subjects and patients with type 2 diabetes mellitus. Macrophage expression of ABCG1 in both patients and control subjects was induced by treatment with the liver X receptor agonist TO-901317. Upregulation of liver X receptor dramatically reduced foam cell formation in macrophages from patients with type 2 diabetes mellitus. ABCG1 expression and cholesterol efflux are reduced in patients with type 2 diabetes mellitus. This impaired ABCG1-mediated cholesterol efflux significantly correlates with increased intracellular cholesterol accumulation. Strategies to upregulate ABCG1 expression and function in type 2 diabetes mellitus could have therapeutic potential for limiting the accelerated vascular disease observed in patients with type 2 diabetes mellitus.