Anti-inflammatory and metabolic actions of FXR: Insights into molecular mechanisms

• Published in: Biochimica et biophysica acta 2012-11, Vol.1821 (11), p.1443-1452
• Main Authors: Hollman, Danielle A.A., Milona, Alexandra, van Erpecum, Karel J., van Mil, Saskia W.C.
• Format: Article
• Language: English
• Subjects: adverse effects; agonists; Anti-Inflammatory Agents - pharmacology; bile acids; Bile Acids and Salts - metabolism; drugs; FXR; genes; glucose; homeostasis; Humans; inflammation; Inflammation - drug therapy; Nuclear receptor; phosphorylation; Post-translational modification; Protein Processing, Post-Translational; receptors; RNA-Binding Proteins - metabolism; Selective ligand; Transactivation; transcription factors; transcriptional activation; Transrepression
• ISSN: 1388-1981; 0006-3002; 1879-2618
• DOI: 10.1016/j.bbalip.2012.07.004

The farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor (NR) superfamily. FXR plays an important role in positively regulating genes (transactivation) involved in bile acid homeostasis, fat and glucose metabolism. Recently, it has become clear that an additional important role for FXR consists of downregulating genes involved in inflammation. Because of this broad spectrum of regulated genes, therapeutically targeting FXR with full agonists will likely result in adverse side effects, in line with what is described for other NRs. It may therefore be necessary to develop selective FXR modulators. However, the molecular mechanisms that distinguish between FXR-mediated transactivation and transrepression are currently unknown. For other NRs, post-translational modifications such as SUMOylation and phosphorylation have been reported to be unique to either transactivation or transrepression. Here, we review current knowledge on post-translational regulation of FXR with respect to transactivation and transrepression. Ultimately, increased understanding of the different mechanisms of transactivation and transrepression of nuclear receptors will aid in the development of NR drugs with fewer side effects. ► FXR transactivates genes involved in bile acid, glucose and fat homeostasis. ► FXR negatively regulates genes (via transrepression) involved in inflammation. ► Therefore, side effects will probably occur when full FXR agonists are used in clinic. ► Post-translational modifications differentiate between transactivation/-repression. ► Unraveling the mechanisms of FXR signaling enables selective FXR ligand design.