Knock-down of the oxysterol receptor LXRα impairs cholesterol efflux in human primary macrophages: Lack of compensation by LXRβ activation
Knock-down of the oxysterol receptor LXRα impairs cholesterol efflux in human primary macrophages: Lack of compensation by LXRβ activation
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DOI：
10.1016/j.bcp.2012.12.024
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发表时间：
2013-07-01
影响因子：
5.8
通讯作者：
Masson, David
中科院分区：
文献类型：
--
作者：
Ishibashi, Minako;Filomenko, Rodolphe;Masson, David
肝脏X受体（LXRs）α和β是参与控制脂质代谢和炎症的氧固醇激活的核受体。LXR的药理学激活在动脉粥样硬化的治疗中是有希望的，因为它可以促进胆固醇从巨噬细胞流出并防止泡沫细胞形成。然而，LXR激动剂的开发受到不期望的副作用如由LXR α活化介导的肝脂肪变性的限制。因此，已经提出将LXR α激活剂靶向肝外组织或使用LXR β特异性激活剂可以用作替代策略。目前尚不清楚这些分子是否会保留非选择性激动剂的全部动脉粥样硬化保护潜力。因此，我们的目的是确定LXR α和LXR β对控制人巨噬细胞中胆固醇流出的贡献。在用或不用合成的LXR α/β双重激动剂T0901317和GW 3965处理的人原代巨噬细胞中，LXR α和/或LXR β表达被小干扰RNA抑制。我们观察到LXR β沉默对LXR靶基因如ABCA 1和ABCG 1的表达没有可检测的影响。此外，它不影响胆固醇流出。相反，LXR α沉默降低了这些LXR靶基因对LXR激动剂的反应，并抑制胆固醇流出至ApoA-I、HDL 2或内源性ApoE。总之，我们的数据表明，当LXR α表达受损时，LXR β激活不能维持人原代巨噬细胞的最大胆固醇流出能力。与早期的小鼠研究相反，LXR α水平似乎是人类巨噬细胞胆固醇流出的限制因素。(C)2013 Elsevier Inc. All rights reserved.
Liver X Receptors (LXRs) alpha and beta are oxysterol-activated nuclear receptors involved in the control of lipid metabolism and inflammation. Pharmacological activation of LXR is promising in the treatment of atherosclerosis since it can promote cholesterol efflux from macrophages and prevent foam cell formation. However, the development of LXR agonists has been limited by undesirable side-effects such as hepatic steatosis mediated by LXR alpha activation. Therefore, it has been proposed that targeting LXR alpha activators to extrahepatic tissues or using LXR beta-specific activators could be used as alternative strategies. It is not clear whether these molecules will retain the full atheroprotective potential of nonselective agonists. Our aim was therefore to determine the contribution of LXR alpha and LXR beta to the control of cholesterol efflux in human macrophages.LXR alpha and/or LXR beta expression was suppressed by small interfering RNAs in human primary macrophages treated or not with synthetic LXR alpha/beta dual agonists T0901317 and GW3965. We observed that LXR beta silencing had no detectable impact on the expression of LXR-target genes such as ABCA1 and ABCG1. Moreover it did not affect cholesterol efflux. In contrast, LXR alpha silencing reduced the response of these LXR-target genes to LXR agonist and inhibited cholesterol efflux to ApoA-I, HDL2 or to endogenous ApoE. Importantly, no differences were observed between LXR alpha and LXR alpha/beta knockdown conditions.Altogether, our data demonstrate that LXR beta activation is unable to maintain maximal cholesterol efflux capacities in human primary macrophages when LXR alpha expression is impaired. In contrast to earlier mouse studies, LXR alpha levels appear as a limiting factor for macrophage cholesterol efflux in humans. (C) 2013 Elsevier Inc. All rights reserved.