Reduced expression of ATP-binding cassette transporter G1 increases cholesterol accumulation in macrophages of patients with type 2 diabetes mellitus.

Abstract

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.

• Authors: Jeremy P Mauldin, Melissa H Nagelin, Allison J Wojcik, Suseela Srinivasan, Marcus D Skaflen, Carlos R Ayers, Coleen A McNamara, Catherine C Hedrick
• Journal: Circulation (Circulation) Vol. 117 Issue 21 Pg. 2785-92 (May 27 2008) ISSN: 1524-4539 [Electronic] United States
• PMID: 18490524 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABCG1 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 1
• ATP-Binding Cassette Transporters
• Cholesterol Esters
• Cholesterol, HDL
• Hydrocarbons, Fluorinated
• Sulfonamides
• T0901317

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 1
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Atherosclerosis (metabolism, physiopathology)
• Cell Differentiation (immunology)
• Cells, Cultured
• Cholesterol Esters (metabolism)
• Cholesterol, HDL (metabolism)
• Diabetes Mellitus, Type 2 (metabolism, physiopathology)
• Diabetic Angiopathies (metabolism, physiopathology)
• Female
• Gene Expression
• Humans
• Hydrocarbons, Fluorinated (pharmacology)
• Macrophages (cytology, drug effects, metabolism)
• Male
• Middle Aged
• Monocytes (cytology, drug effects, metabolism)
• Sulfonamides (pharmacology)