van Mil group:
The role of the nuclear receptor FXR in gastro-intestinal disease
PI: Saskia W.C. van Mil (about the group leader)
Nuclear receptors (NRs) are ligand-activated transcription factors that play vital roles in growth, development and homeostasis. 13% of all FDA-approved drugs target NRs, however they are associated with serious side-effects, due to general activation of all transcriptional actions of NRs. We aim to obtain fundamental knowledge on the molecular mechanisms of different NR transcriptional functions, essential to improve rational NR drug design and evaluation.
We focus on FXR, the NR activated by bile salts and key regulator of bile salt, cholesterol, lipid and glucose metabolism via classical transactivation. Secondly, FXR also regulates inflammation status most probably via transrepression of NF-kB. Thirdly, FXR function is repressed during pregnancy, explaining why genetically susceptible women develop liver impairment during pregnancy.
We are functionally dissecting the different molecular mechanisms of FXR action in these physiological settings: i. FXR transactivation, ii. FXR transrepression and iii. FXR inhibition (pregnancy). We are addressing the following objectives:
1. Investigate the upstream protein modifications in FXR
2. Investigate the protein-protein interactions that govern FXR signaling
3. Generate and evaluate in vitro and in vivo model systems of modifications and recruited proteins that distinguish these physiological settings.
We use novel unbiased high-throughput assay that combines SILAC and biotinylated DNA-protein complex precipitations to identify modifications and interacting proteins by highly sensitive Mass Spectrometry.
Detailed molecular insights by which FXR integrates metabolic, endocrine and inflammatory signaling will advance drug design for FXR in particular and NRs in general.