Transactivation versus transrepression in FXR: lessons learned from other Nuclear Receptors

Abstract

Farnesoid X Receptor (FXR) is an important player in the upregulation of genes (transactivation) in bile acid homeostasis and fat and glucose metabolism. Recently, it has become clear that an additional important role for FXR consists of downregulating genes (transrepression) in inflammation. Because of this dual role of FXR, full agonists will likely have serious side effects, which would be similar to what is known for other members of the Nuclear Receptor (NR) family. Therefore selective modulators of FXR should be developed. However, the molecular mechanisms deciding between transactivation and transrepression in FXR are currently unknown. For the NR family, cases of SUMOylation and phosphorylation have been reported to be distinctive between transactivation and transrepression. SUMOylation can either diminish transactivation selectively or increase transrepression. Phosphorylation was observed to prime for SUMOylation, thereby also selectively augmenting transrepression. Here, we review the state of current knowledge about FXR transactivation and transrepression and compare this to what is known in other members of the NR family. Ultimately, increased knowledge on the differential mechanisms of transactivation and transrepression will lead to the development of more specific drugs with less serious side effects.