Identification of a novel liver X receptor agonist that regulates the expression of key cholesterol homeostasis genes with distinct pharmacological characteristics

Abstract

Activation of liver X receptor (LXR) is associated with cholesterol metabolism and anti-inflammatory processes, which makes it beneficial to antiatherosclerosis therapy. Nevertheless, existing agonists that 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 LXRa/b 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 with the full LXR agonist TO901317, IMB-808 recruits coregulators differently and possesses a 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 that avoids 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.