Identification of a novel partial agonist of liver X receptor α(LXRα)via screening
Liver X receptor α(LXRα)plays an important role in the cholesterol metabolism process,and LXRα activation can reduce atherosclerosis.In the present study,using an LXRα-GAL4 luciferase reporter screening,we discovered IMB-170,a structural analog of quinazolinone,which showed potent LXRα agonistic activity,IMB-170 significantly activated LXRα,with an EC50 value of 0.27 μM.interestingly,IMB-170 not only increased the expression of ATP-binding cassette transporter A1(ABCA1)and G1(ABCG1),which are related to the reverse thole sterol 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 accomolation and increased cholesterol efflox from RAW264.7 and THP-1 macrophages.Interestingly,compared with T0901317,”MB-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 LXRα.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 LXRα ligand-binding domain.In summary.IMB-170 is a novel partial LXRα agonist without the classical lipogenesis side effects,which could be used as a potential anti-atherosclerotic leading compound in the future.
LXRα Atherosclerosis Cholesterol efflux Partial agonist
Ni Li Xiao Wang Jing Zhang Chang Liu Yongzhen Li Tingting Feng Yanni Xu Shuyi Si
Institute of Medicinal Biotechnology,Chinese Academy of Medicat Sciences and Peking Union Medical Co Institute of Medicinal Biotechnology,Chinese Academy of Medicat Sciences and Peking Union Medical Co
国内会议
大连
英文
390-399
2016-09-24（万方平台首次上网日期，不代表论文的发表时间）