Molecular mechanisms responsible for the reduced expression of cholesterol transporters from macrophages by low-dose endotoxin.
Molecular mechanisms responsible for the reduced expression of cholesterol transporters from macrophages by low-dose endotoxin.
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DOI：
10.1161/atvbaha.112.300049
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发表时间：
2013-01
期刊：
影响因子：
--
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Maitra U;Li L
动脉粥样硬化的特征是一种慢性炎症性疾病，涉及动脉中的胆固醇沉积。与清道夫受体B1（SR-B1）一起，ATP结合盒转运体ABCA 1和ABCG 1是巨噬细胞胆固醇流出的主要组分。最近的研究表明，低度炎症对SR-B1和ABCA 1/ABCG 1的表达起着独特的调节作用。然而，低度炎症和胆固醇蓄积之间的联系机制尚不清楚。使用原代骨髓源性巨噬细胞，我们证明亚临床低剂量脂多糖（LPS）有效地降低SR-B1和ABCA 1/ABCG 1的表达，以及通过白细胞介素-1受体相关激酶1（IRAK-1）和Toll相互作用蛋白（Tollip）从巨噬细胞中流出的胆固醇。低剂量LPS下调视黄酸受体RARα的核水平，导致其与SR-B1和ABCA 1/ABCG 1启动子的结合减少。我们观察到低剂量LPS通过IRAK 1和Tollip激活糖原合成酶激酶3β（GSK 3 β）导致RARα水平降低以及SR-B1和ABCA 1/ABCG 1表达降低。另一方面，IRAK-M会抵消IRAK-1的功能。总的来说，我们的数据揭示了一种新的细胞内网络调节低剂量内毒素血症，破坏胆固醇流出巨噬细胞，导致动脉粥样硬化的发病机制。
Atherosclerosis is characterized as a chronic inflammatory condition that involves cholesterol deposition in arteries. Together with scavenger receptor B1 (SR-B1), the ATP-binding cassette transporters ABCA1 and ABCG1 are the major components of macrophage cholesterol efflux. Recent studies have shown that low grade inflammation plays a distinct regulatory role in the expression of SR-B1 and ABCA1/ABCG1. However, the mechanisms linking low grade inflammation and cholesterol accumulation are poorly understood. Using primary bone marrow-derived macrophages, we demonstrate that subclinical low dose lipopolysaccharide (LPS) potently reduces the expression of SR-B1 and ABCA1/ABCG1, as well as cholesterol efflux from macrophages through interleukin-1 receptor associated kinase 1 (IRAK-1) and toll-interacting-protein (Tollip). Low dose LPS down-regulates the nuclear levels of retinoic acid receptor RARα leading to their reduced binding to the promoters of SR-B1 and ABCA1/ABCG1. We observe that glycogen synthase kinase 3β (GSK3β) activation by low dose LPS through IRAK1 and Tollip is responsible for reduced levels of RARα and reduced expression of SR-B1 and ABCA1/ABCG1. IRAK-M, on the other hand, counteracts the function of IRAK-1. Collectively, our data reveal a novel intracellular network regulated by low dose endotoxemia that disrupts cholesterol efflux from macrophages and leads to the pathogenesis of atherosclerosis.