Development of novel sterol-based Liver X Receptor agonists as therapeutics for inflammatory diseases (HUM1P.307)

• Published in: The Journal of immunology (1950) 2015-05, Vol.194 (1_Supplement), p.52-52.32
• Main Authors: Yu, Shan, Li, Shangjin, Henke, Adam, Welzel, Gustav, Li, Sijia, Cheng, Bo, Evan, Muse, Glass, Christopher, Chatterjee, Arnab, Roland, Jason, Schultz, Peter, Tremblay, Matthew
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.194.Supp.52.32

Liver X Receptor (LXR), a nuclear hormone receptor, is an essential regulator of immune responses. Activation of LXR by synthetic agonists, including T0901317 and GW3965, attenuates progression of inflammatory diseases of animal models. However, the adverse effects of traditional LXR agonists in elevating liver lipids have impeded exploitation of this intriguing mechanism for chronic therapy. The endogenous LXR agonist desmosterol and its sterol-based analog DMHCA activate LXR without the lipogenic action in the liver - this inspired us to develop anti-inflammatory therapies based on these analogs. Here, we show DMHCA oral treatment in mice significantly reduce DSS colitis-induced body weight loss, which is accompanied by reduced expression of inflammatory markers in the large intestine. This reduced inflammation is associated with induced LXR target gene expression, suggesting DMHCA attenuating colitis is mediated, at least partially, through LXR activation. In addition, DMHCA treatment dramatically suppresses inflammatory cytokine expression in traumatic brain injury model. Importantly, in both disease models, DMHCA does not increase liver lipid or serum ALT levels, while T0901317 results in significant liver lipid accumulation and injury. The anti-inflammatory property of DMHCA is recapitulated in vitro in CD3/CD28 activated human PBMCs. Overall, these results provide evidence for the development of sterol-based LXR agonists as novel therapeutics for inflammatory diseases.