Liver X receptors (LXRs) are members of nuclear receptor superfamily with two subtypes, LXR alpha and LXR beta. Physiological LXRs agonists (oxysterols) activate the transcription of target genes including ATP binding cassettes (abca1, abcg1) in macrophages, and prevent cholesterol accumulation. However, they also induce hypertriglyceridemia in the liver, mainly through the upregulation of sterol regulatory binding element protein 1c (srebp-1c). This LXR-mediated activation of gene transcription is called transactivation.
On the other hands, it is reported that some LXR agonists inhibit the gene expression of interleukin-6 (il-6), interleukin-1beta (il-1beta), and inducible nitric oxide synthase (inos). This function of LXR is thought to be independent of transactivation, and is called transrepression. LXR ligands possessing transrepressional activity might be anti-inflammatory drugs, but transactivation effect would cause hypertriglyceridemia. Then, we aim to separate these two effects, and develop transrepression-selective LXR ligands.
We found some styrylphenyl phthalimides show transrepressional activity, and their structural modification led to a series of compounds possessing potent transrepression but no transactivation in reporter gene assay. In qPCR, the compounds didn't induce abca1 and srebp-1c in cells. TR-FRET binding assay indicated that they bind directly to LXR. These compounds should be useful for both chemical tools and safer candidate agents for treatment of inflammatory diseases.
Recently, it has been reported that Liver X receptors non-selective agonists suppress NLRP3 inflammasome activation. Thus, the regulation of LXRs signaling is a potential therapeutic for NLRP3-driven diseases. We hypothesized that our selective ligands could be a chemical tool for analyzing this mechanism. Then, we analyzed the effect of our transrepression-selective LXR ligands and LXR β selective ligand for the mouse micloglia cells (6-3 cells) by means of IL-1β ELISA assay and show the date in this poster.