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

Danielle A A Hollman1, Alexandra Milona, Karel J van Erpecum

  • 1Department of Metabolic Diseases, UMC Utrecht and Netherlands Metabolomics Centre, The Netherlands.

Biochimica Et Biophysica Acta
|July 24, 2012
PubMed

Insights

Farnesoid X receptor (FXR) regulates genes for metabolism and inflammation. Understanding its distinct transactivation and transrepression mechanisms is key to developing selective modulators with fewer side effects.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • The farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, fat, and glucose metabolism.
  • FXR also plays a critical role in downregulating inflammatory gene expression.
  • Targeting FXR therapeutically is complex due to its diverse gene regulation, necessitating selective modulators.

Purpose of the Study:

  • To review the current understanding of post-translational modifications in FXR-mediated transactivation and transrepression.
  • To elucidate the molecular mechanisms distinguishing FXR's opposing regulatory functions.
  • To inform the development of safer and more effective FXR-targeted therapies.

Main Methods:

  • Literature review of studies on FXR post-translational modifications.
  • Analysis of SUMOylation and phosphorylation roles in nuclear receptor function.
  • Comparative examination of transactivation versus transrepression mechanisms.

Main Results:

  • FXR mediates both gene transactivation (metabolism) and transrepression (inflammation).
  • Post-translational modifications like SUMOylation and phosphorylation are implicated in differentiating these functions for other nuclear receptors.
  • Specific mechanisms for FXR transactivation/transrepression remain largely uncharacterized.

Conclusions:

  • Selective FXR modulators are needed to mitigate side effects associated with full agonists.
  • Understanding post-translational regulation is crucial for distinguishing FXR's transactivation and transrepression pathways.
  • Further research into these mechanisms will facilitate the design of improved nuclear receptor drugs with enhanced safety profiles.

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