Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages
Regulation of retinoid mediated cholesterol efflux involves liver X receptor activation in mouse macrophages
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DOI：
10.1016/j.bbrc.2015.06.150
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发表时间：
2015-08-14
影响因子：
3.1
通讯作者：
Pruitt, Kevin
中科院分区：
文献类型：
--
作者：
Manna, Pulak R.;Sennoune, Souad R.;Pruitt, Kevin
从巨噬细胞源性泡沫细胞中去除胆固醇是预防动脉粥样硬化病变的关键步骤。我们最近证明了类维生素A在调节类固醇生成急性调节（星星）蛋白中的功能重要性，该蛋白主要介导胆固醇在靶组织中的线粒体内转运。在本研究中，用类维生素A，特别是全反式维甲酸（atRA）和9-顺式RA处理小鼠巨噬细胞，导致胆固醇流出到载脂蛋白Al（Apo-Al）的增加。通过cAMP类似物（Bu）（2）cAMP激活PKA通路，可显著增加类维生素A介导的胆固醇流出。巨噬细胞过度表达对胆固醇敏感的脂肪酶增加了胆固醇酯的水解，同时增强了视黄酸受体和肝X受体（LXR）配体对星星和ATP结合盒转运蛋白Al（ABCA 1）蛋白水平的作用。RA提高了巨噬细胞中星星启动子的活性，并且星星水平的增加增强了胆固醇向Apo-Al的流出，这表明类维生素A介导的胆固醇流出涉及增强的氧固醇产生。进一步的研究表明，类维生素A激活LXR调节基因，固醇受体元件结合蛋白-1c和ABCA 1。这些研究结果提供了深入了解的调节事件，其中类维生素A信号有效地增强巨噬细胞胆固醇流出，并表明类维生素A治疗可能有重要意义的限制和/或消退动脉粥样硬化性心血管疾病。(C)2015 Elsevier Inc. All rights reserved.
Removal of cholesterol from macrophage-derived foam cells is a critical step to the prevention of atherosclerotic lesions. We have recently demonstrated the functional importance of retinoids in the regulation of the steroidogenic acute regulatory (StAR) protein that predominantly mediates the intra-mitochondrial transport of cholesterol in target tissues. In the present study, treatment of mouse macrophages with retinoids, particularly all-trans retinoic acid (atRA) and 9-cis RA, resulted in increases in cholesterol efflux to apolipoprotein Al (Apo-Al). Activation of the PKA pathway by a CAMP analog, (Bu)(2)cAMP, markedly augmented retinoid mediated cholesterol efflux. Macrophages overexpressing hormone-sensitive lipase increased the hydrolysis of cholesteryl esters and concomitantly enhanced the efficacy of retinoic acid receptor and liver X receptor (LXR) ligands on StAR and ATP-binding cassette transporter Al (ABCA1) protein levels. RAs elevated StAR promoter activity in macrophages, and an increase in StAR levels augmented cholesterol efflux to Apo-Al, suggesting retinoid-mediated efflux of cholesterol involves enhanced oxysterol production. Further studies revealed that retinoids activate the LXR regulated genes, sterol receptor-element binding protein-1c and ABCA1. These findings provide insights into the regulatory events in which retinoid signaling effectively enhances macrophage cholesterol efflux and indicate that retinoid therapy may have important implications in limiting and/or regressing atherosclerotic cardiovascular disease. (C) 2015 Elsevier Inc. All rights reserved.