title: Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.
abstract: Liver X receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR-mediated transcription by synthetic agonists, such as T0901317 and GW3965, attenuates progression of inflammatory disease in animal models. However, the adverse effects of these conventional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. Here, we explore the ability of a series of sterol-based LXR agonists to alleviate inflammatory conditions in mice without hepatotoxicity. We show that oral treatment with sterol-based LXR agonists in mice significantly reduces dextran sulfate sodium colitis-induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. The anti-inflammatory property of these agonists is recapitulated in vitro in mouse lamina propria mononuclear cells, human colonic epithelial cells, and human peripheral blood mononuclear cells. In addition, treatment with LXR agonists dramatically suppresses inflammatory cytokine expression in a model of traumatic brain injury. Importantly, in both disease models, the sterol-based agonists do not affect the liver, and the conventional agonist T0901317 results in significant liver lipid accumulation and injury. Overall, these results provide evidence for the development of sterol-based LXR agonists as novel therapeutics for chronic inflammatory diseases.-Yu, S., Li, S., Henke, A., Muse, E. D., Cheng, B., Welzel, G., Chatterjee, A. K., Wang, D., Roland, J., Glass, C. K., Tremblay, M. Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA;
authors.forename: Shan
authors.initials: S
authors.lastname: Yu
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA;
authors.forename: Sijia
authors.initials: S
authors.lastname: Li
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA;
authors.forename: Adam
authors.initials: A
authors.lastname: Henke
authors.affiliation: Department of Cellular and Molecular Medicine and Scripps Translational Science Institute, Scripps Health, La Jolla, California, USA and.
authors.forename: Evan D
authors.initials: ED
authors.lastname: Muse
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA;
authors.forename: Bo
authors.initials: B
authors.lastname: Cheng
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA;
authors.forename: Gustav
authors.initials: G
authors.lastname: Welzel
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA;
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA;
authors.forename: Danling
authors.initials: D
authors.lastname: Wang
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA;
authors.forename: Jason
authors.initials: J
authors.lastname: Roland
authors.affiliation: Department of Cellular and Molecular Medicine and Department of Medicine, University of California, San Diego, La Jolla, California, USA; and cglass@ucsd.edu.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
authors.affiliation: California Institute for Biomedical Research, La Jolla, California, USA; mtremblay@calibr.org.
authors.forename: Matthew
authors.initials: M
authors.lastname: Tremblay
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy*; D003106:Colon / Q000166:cytology; D016264:Dextran Sulfate / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006845:Hydrocarbons, Fluorinated / Q000009:adverse effects / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors / Q000819:agonists*; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D013261:Sterols / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D016264:Dextran Sulfate; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D013261:Sterols; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: LXR; drug discovery; traumatic brain injury; ulcerative colitis