Ma A Zhi Sha, Song Zhi Yuan, Zhang Qian
Department of Cardiology, Southwest Hospital, The Third Military Medical University, Chongqing, China.
BMC Cardiovasc Disord. 2014 Jul 4;14:80. doi: 10.1186/1471-2261-14-80.
The nuclear receptor liver X receptor (LXR) has two isoforms: LXRα and LXRβ. LXR activation promotes cholesterol efflux in macrophages, but the relative importance of each LXR isoform in mediating cholesterol efflux remains elusive.
We evaluated the ability of different doses of LXRs agonist T0901317 to affect cholesterol efflux in human macrophages and its relationship with mRNA and protein levels of several well-characterized proteins involved in cholesterol efflux, including ABCA1, ABCG1, SR-BI, LXRβ and LXRα, using quantitative real-time PCR, Western blotting, and siRNA techniques.
Here we show that LXRα rather than LXRβ sustains baseline cholesterol efflux in human blood-derived macrophages. Treatment of human macrophages with a non-isoform-specific LXR agonist T0901317 substantially increased HDL- and apoA-I-mediated cholesterol efflux, which was associated with increased mRNA and protein expression levels of ABCA1, ABCG1, SR-BI, LXRα and LXRβ. The siRNA- mediated silencing of LXRα, but not LXRβ significantly reduced the protein levels of ABCA1,ABCG1, and SR-BI as wellas HDL- and ApoA1-mediated cholesterol in human macrophages.
These findings imply that LXRα- rather than LXRβ- specific agonists may promote reverse cholesterol transport in humans.
核受体肝X受体（LXR）有两种亚型：LXRα和LXRβ。LXR激活可促进巨噬细胞中的胆固醇流出，但每种LXR亚型在介导胆固醇流出中的相对重要性仍不清楚。
我们使用定量实时PCR、蛋白质印迹和小干扰RNA技术，评估不同剂量的LXR激动剂T0901317影响人巨噬细胞中胆固醇流出的能力，以及它与几种参与胆固醇流出的特征明确的蛋白质的mRNA和蛋白质水平的关系，这些蛋白质包括ABCA1、ABCG1、SR-BI、LXRβ和LXRα。
我们在此表明，在源自人血液的巨噬细胞中，维持基线胆固醇流出的是LXRα而非LXRβ。用非亚型特异性LXR激动剂T0901317处理人巨噬细胞，可显著增加高密度脂蛋白（HDL）和载脂蛋白A-I（apoA-I）介导的胆固醇流出，这与ABCA1、ABCG1、SR-BI、LXRα和LXRβ的mRNA和蛋白质表达水平增加有关。小干扰RNA介导的LXRα而非LXRβ沉默，可显著降低人巨噬细胞中ABCA1、ABCG1和SR-BI的蛋白质水平以及HDL和载脂蛋白A1介导的胆固醇水平。
这些发现表明，LXRα特异性而非LXRβ特异性激动剂可能促进人类的胆固醇逆向转运。
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