title: 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 LXRα/βagonistic 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.
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, People's Republic of China (N.L., Y.L., D.L.); and Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China (N.L., X.W., Y.X., N.Z., P.L., S.S.).
authors.forename: Ni
authors.initials: N
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, People's Republic of China (N.L., Y.L., D.L.); and Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China (N.L., X.W., Y.X., N.Z., P.L., S.S.).
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, People's Republic of China (N.L., Y.L., D.L.); and Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China (N.L., X.W., Y.X., N.Z., P.L., S.S.).
authors.forename: Yanni
authors.initials: Y
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, People's Republic of China (N.L., Y.L., D.L.); and Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China (N.L., X.W., Y.X., N.Z., P.L., S.S.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, People's Republic of China (N.L., Y.L., D.L.); and Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China (N.L., X.W., Y.X., N.Z., P.L., S.S.).
authors.forename: Ningyu
authors.initials: N
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, People's Republic of China (N.L., Y.L., D.L.); and Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China (N.L., X.W., Y.X., N.Z., P.L., S.S.).
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, People's Republic of China (N.L., Y.L., D.L.); and Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China (N.L., X.W., Y.X., N.Z., P.L., S.S.) sisyimb@hotmail.com luduo@imm.ac.cn.
authors.forename: Duo
authors.initials: D
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences, Beijing, People's Republic of China (N.L., Y.L., D.L.); and Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China (N.L., X.W., Y.X., N.Z., P.L., S.S.) sisyimb@hotmail.com luduo@imm.ac.cn.
authors.forename: Shuyi
authors.initials: S
authors.lastname: Si
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D020134:Catalytic Domain; D002784:Cholesterol / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008077:Lipoproteins, LDL / Q000494:pharmacology; D000071518:Liver X Receptors / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D062105:Molecular Docking Simulation; D009154:Mutation / Q000235:genetics; D000072417:Protein Domains; D000067996:RAW 264.7 Cells; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D001569:Benzodiazepines; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C099252:oxidized low density lipoprotein