Selective targeting of nuclear receptors
NRs are ligand-activated transcription factors important for human physiology. FXR (farnesoid X receptor, also known as bile acid receptor) is a nuclear receptor activated by bile acids. It is expressed at high levels in liver and intestinal tissues. FXR regulates the transcription of genes involved in bile salt, cholesterol, lipid and glucose homeostasis by classical transactivation mechanisms. FXR also regulates inflammation, supposedly through FXR-mediated transrepression of NF-kB. FXR is a potential therapeutic target for cholestasis, diabetes and inflammatory diseases of the gastrointestinal tract. The EU-funded project MECHFXR investigated FXR action in detail. The project focused on post-translational modifications of FXR and how they lead to different biological responses. Discriminating between transactivation and transrepression was important as the first one relates to anti-cholestatic and metabolic FXR effects, and the latter to its inflammatory actions. Novel post-translational modifications in FXR were found, including three acetylation sites and a phosphorylation site. Phosphorylation was shown to be important for transactivation of FXR target genes, but not NF-kB transrepression in vitro. Thus, selective FXR ligands not resulting in phosphorylation have a potential to treat intestinal inflammation without interfering with bile salt, glucose and fat metabolism. A high-throughput screening assay to identify anti-inflammatory FXR ligands, which allow transrepression of NF-kB signalling without affecting transactivation capacities of FXR, was set up. Using a luciferase assay, the compounds from chemical libraries were screened for their capacity to modulate FXR function. In addition, scientists explored FXR involvement in novel pathways and diseases. Both cooperative and independent interactions between FXR and oestrogen receptor alpha in regulating gene transcription in the liver were demonstrated. Understanding different molecular mechanisms of FXR during ligand-dependent transactivation and transrepression will allow the improvement of NR drug design and efficacy.
Keywords
Nuclear receptors, transcription factors, farnesoid X receptor, bile acid, transrepression
