Format

Send to

Choose Destination
FASEB J. 2016 Jul;30(7):2570-9. doi: 10.1096/fj.201600244R. Epub 2016 Mar 29.

Dissociated sterol-based liver X receptor agonists as therapeutics for chronic inflammatory diseases.

Author information

1
California Institute for Biomedical Research, La Jolla, California, USA;
2
Department of Cellular and Molecular Medicine and Scripps Translational Science Institute, Scripps Health, La Jolla, California, USA and.
3
Department of Cellular and Molecular Medicine and Department of Medicine, University of California, San Diego, La Jolla, California, USA; and cglass@ucsd.edu.
4
California Institute for Biomedical Research, La Jolla, California, USA; mtremblay@calibr.org.

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.

KEYWORDS:

LXR; drug discovery; traumatic brain injury; ulcerative colitis

PMID:
27025962
PMCID:
PMC4904286
DOI:
10.1096/fj.201600244R
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center