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(Circulation. 2008;117:2785-2792.)
© 2008 American Heart Association, Inc.

Vascular Medicine

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

Jeremy P. Mauldin, PhD; Melissa H. Nagelin, MS; Allison J. Wojcik, MS; Suseela Srinivasan, PhD; Marcus D. Skaflen, BS; Carlos R. Ayers, MD; Coleen A. McNamara, MD; Catherine C. Hedrick, PhD

From the Cardiovascular Research Center (J.P.M., M.H.N., A.J.W., S.S., M.D.S., C.A.M., C.C.H.), Department of Pharmacology (J.P.M., M.H.N., A.J.W., C.C.H.), and Department of Internal Medicine (C.R.A., C.A.M., C.C.H.), University of Virginia, Charlottesville.

Correspondence to Catherine C. Hedrick, PhD, Cardiovascular Research Center, University of Virginia, 415 Lane Rd, Bldg MR-5, Room G123, PO Box 801394, Charlottesville, VA 22908. E-mail cch6n{at}virginia.edu

Received September 20, 2007; accepted April 2, 2008.

Background— 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.

Methods and Results— 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.

Conclusions— 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.

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CLINICAL PERSPECTIVE

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