TY - JOUR T1 - Identification of a novel liver X receptor agonist that regulates the expression of key cholesterol homeostasis genes with distinct pharmacological characteristics JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.116.105213 SP - mol.116.105213 AU - Ni Li AU - Xiao Wang AU - Yanni Xu AU - Yuan Lin AU - Ningyu Zhu AU - Peng Liu AU - Duo Lu AU - Shuyi Si Y1 - 2017/01/01 UR - http://molpharm.aspetjournals.org/content/early/2017/01/13/mol.116.105213.abstract N2 - Activation of Liver X receptor (LXR) is associated with cholesterol metabolism and anti-inflammatory processes, which makes beneficial to anti-atherosclerosis. Nevertheless, existing agonists which target LXR, for example TO901317, are related to unwanted side-effects. In the present study, using a screening method we identified IMB-808, which displayed potent dual LXRα/β agonistic activity. In vitro, IMB-808 effectively increased the expressing quantity of genes related to reverse cholesterol transport process as well as those associated with cholesterol metabolism pathway in multiple cell lines. Additionally, IMB-808 remarkably promoted cholesterol efflux from RAW264.7 as well as THP-1 macrophage cells and reduced cellular lipid accumulation accordingly. Interestingly, compared with TO901317, IMB-808 almost did not increase the expressing quantity of genes related to lipogenesis in HepG2 cells, which indicated that IMB-808 could exhibit fewer internal lipogenic side-effects with a characteristic of selective LXR agonist. Furthermore, in comparison to the full LXR agonist TO901317, IMB-808 recruits co-regulators differently and possesses distinct predictive binding pattern for the LXR ligand-binding domain. In summary, our study demonstrated that IMB-808 could act as an innovative partial LXR agonist avoiding common lipogenic side-effects, providing insight for the design of novel LXR modulators. Our data indicate that this compound might be used as a promising therapeutic agent for the prospective treatment of atherosclerosis in the future. ER -