Identification of a novel partial agonist of liver X receptor α (LXRα) via screening
Identification of a novel partial agonist of liver X receptor α (LXRα) via screening
复制标题
DOI：
10.1016/j.bcp.2014.09.017
复制
发表时间：
2014-12-01
影响因子：
5.8
通讯作者：
Si, Shuyi
中科院分区：
文献类型：
--
作者：
Li, Ni;Wang, Xiao;Si, Shuyi
肝脏X受体α（LXR α）在胆固醇代谢过程中起着重要作用，LXR α激活可以减少动脉粥样硬化。在本研究中，使用LXR α-GAL 4荧光素酶报告基因筛选，我们发现了IMB-170，一种喹唑啉酮的结构类似物，其显示出有效的LXR α激动活性。IMB-170显著激活LXR α，EC 50值为0.27 μ M。有趣的是，IMB-170不仅增加与胆固醇逆向转运（RCT）过程相关的ATP结合盒转运蛋白A1（ABCA 1）和G1（ABCG 1）的表达，而且还影响许多细胞系中参与胆固醇代谢途径的其他基因的表达水平。此外，IMB-170显著减少细胞脂质积累并增加来自RAW 264.7和THP-1巨噬细胞的胆固醇流出。有趣的是，与T0901317相比，IMB-170仅轻微增加HepG 2细胞中脂肪生成相关基因的蛋白表达水平，表明IMB-170可能具有较低的体内脂肪生成副作用。这些结果表明，IMB-170显示出对LXRa的选择性激动活性。此外，与完整的LXR激动剂相比，IMB-170具有不同的募集辅调节因子的能力。这表明IMB-170与LXRa配体结合结构域中的活性位点具有不同的相互作用。综上所述，IMB-170是一种新型的LXR α部分激动剂，没有经典的脂肪生成副作用，可以作为未来潜在的抗动脉粥样硬化的先导化合物。(C)2014爱思唯尔公司All rights reserved.
Liver X receptor a (LXR alpha) plays an important role in the cholesterol metabolism process, and LXRa activation can reduce atherosclerosis. In the present study, using an LXR alpha-GAL4 luciferase reporter screening, we discovered IMB-170, a structural analog of quinazolinone, which showed potent LXRa agonistic activity. IMB-170 significantly activated LXRa, with an EC50 value of 0.27 mu M. Interestingly, IMB-170 not only increased the expression of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1), which are related to the reverse cholesterol transport (RCT) process, but also influenced the expression levels of other genes involved in the cholesterol metabolism pathway in many cell lines. Moreover, IMB-170 significantly reduced cellular lipid accumulation and increased cholesterol efflux from RAW264.7 and THP-1 macrophages. Interestingly, compared with T0901317, IMB-170 only slightly increased protein expression levels of lipogenesis-related genes in HepG2 cells, indicating that IMB-170 may have a lower lipogenesis Side effect in vivo. These results suggest that IMB-170 showed the selective agonistic activity for LXRa. Moreover, compared with full LXR-agonists, IMB-170 possesses a differential ability to recruit coregulators. This suggests that IMB-170 has distinct interactions with the active sites in the LXRa ligand-binding domain. In summary, IMB-170 is a novel partial LXRa agonist without the classical lipogenesis side effects, which could be used as a potential anti-atherosclerotic leading compound in the future. (C) 2014 Elsevier Inc. All rights reserved.