LXR-Mediated ABCA1 Expression and Function Are Modulated by High Glucose and PRMT2.
LXR-Mediated ABCA1 Expression and Function Are Modulated by High Glucose and PRMT2.
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DOI：
10.1371/journal.pone.0135218
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Garabedian MJ
中科院分区：
文献类型：
--
作者：
Hussein MA;Shrestha E;Ouimet M;Barrett TJ;Leone S;Moore KJ;Hérault Y;Fisher EA;Garabedian MJ
高胆固醇和糖尿病是动脉粥样硬化的主要危险因素。动脉粥样硬化的消退部分由肝X受体（LXR）通过诱导参与胆固醇转运和流出的基因介导。在糖尿病的情况下，动脉粥样硬化的消退受损。我们提出葡萄糖水平的变化调节LXR依赖的基因表达。使用小鼠巨噬细胞系（RAW 264.7）和原代骨髓衍生的巨噬细胞（BMDM）在正常或糖尿病相关的高葡萄糖条件下培养，我们发现，高葡萄糖抑制LXR依赖的表达ATP结合盒转运蛋白A1（ABCA 1），但不ABCG 1。为了探索这种机制，我们调查了染色质修饰酶的宿主的表达，发现蛋白质精氨酸甲基转移酶2（PRMT 2）与正常葡萄糖条件相比在高水平下降低。重要的是，与野生型BMDM相比，Prmt 2-/-中ABCA 1表达和ABCA 1介导的胆固醇流出减少。与非糖尿病小鼠相比，来自糖尿病小鼠的单核细胞也显示Prmt 2表达降低。因此，PRMT 2代表葡萄糖敏感性因子，其在LXR介导的ABCA 1依赖性胆固醇流出中起作用，并有助于了解糖尿病患者中动脉粥样硬化增加的存在。
High cholesterol and diabetes are major risk factors for atherosclerosis. Regression of atherosclerosis is mediated in part by the Liver X Receptor (LXR) through the induction of genes involved in cholesterol transport and efflux. In the context of diabetes, regression of atherosclerosis is impaired. We proposed that changes in glucose levels modulate LXR-dependent gene expression. Using a mouse macrophage cell line (RAW 264.7) and primary bone marrow derived macrophages (BMDMs) cultured in normal or diabetes relevant high glucose conditions we found that high glucose inhibits the LXR-dependent expression of ATP-binding cassette transporter A1 (ABCA1), but not ABCG1. To probe for this mechanism, we surveyed the expression of a host of chromatin-modifying enzymes and found that Protein Arginine Methyltransferase 2 (PRMT2) was reduced in high compared to normal glucose conditions. Importantly, ABCA1 expression and ABCA1-mediated cholesterol efflux were reduced in Prmt2 -/- compared to wild type BMDMs. Monocytes from diabetic mice also showed decreased expression of Prmt2 compared to non-diabetic counterparts. Thus, PRMT2 represents a glucose-sensitive factor that plays a role in LXR-mediated ABCA1-dependent cholesterol efflux and lends insight to the presence of increased atherosclerosis in diabetic patients.