Reduced expression of ATP-binding cassette transporter G1 increases cholesterol accumulation in macrophages of patients with type 2 diabetes mellitus
Reduced expression of ATP-binding cassette transporter G1 increases cholesterol accumulation in macrophages of patients with type 2 diabetes mellitus
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DOI：
10.1161/circulationaha.107.741314
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发表时间：
2008-05-27
期刊：
影响因子：
37.8
通讯作者：
Hedrick, Catherine C.
中科院分区：
文献类型：
--
作者：
Mauldin, Jeremy P.;Nagelin, Melissa H.;Hedrick, Catherine C.
2型糖尿病患者发生动脉粥样硬化的风险增加。动脉粥样硬化发展中的关键事件是巨噬细胞泡沫细胞形成。ATP结合盒（ABC）转运蛋白ABCA 1和ABCG 1调节巨噬细胞胆固醇流出，因此在巨噬细胞泡沫细胞形成中起重要作用。我们以前发现，慢性血糖升高会降低ABCG 1的表达。在本研究中，我们研究了2型糖尿病患者是否有减少ABCG 1和/或ABCA 1，受损的胆固醇流出，并增加巨噬细胞泡沫细胞形成。将外周血单核细胞分化为巨噬细胞，并进行胆固醇流出试验、免疫印迹、组织学分析和细胞内胆固醇酯测量。与对照组相比，2型糖尿病患者的巨噬细胞胆固醇流出减少30%，胆固醇蓄积相应增加60%。ABCG 1存在于对照受试者的巨噬细胞中，但在2型糖尿病患者的巨噬细胞中检测不到。相比之下，ABCA 1在巨噬细胞中的表达在对照组和2型糖尿病患者中相似。通过用肝X受体激动剂TO-901317治疗诱导患者和对照受试者中ABCG 1的巨噬细胞表达。上调肝脏X受体显着减少泡沫细胞形成巨噬细胞从2型糖尿病mellitus. Conclusions-ABCG 1的表达和胆固醇流出减少2型糖尿病患者。这种受损的ABCG 1介导的胆固醇流出与细胞内胆固醇积累增加显著相关。在2型糖尿病中上调ABCG 1表达和功能的策略可能具有限制在2型糖尿病患者中观察到的加速血管疾病的治疗潜力。
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.