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Recent advances on FXR-targeting therapeutics

Katrin Panzitt1, Gernot Zollner2, Hanns-Ulrich Marschall3

  • 1Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.

Molecular and Cellular Endocrinology
|May 23, 2022
PubMed

Insights

Targeting the Farnesyl X Receptor (FXR) shows promise for liver diseases. Selective intestinal FXR activation may offer benefits over broad activation, potentially reducing side effects for metabolic and cholestatic conditions.

Area of Science:

  • Pharmacology and Gastroenterology
  • Hepatology and Metabolic Diseases

Background:

  • The bile acid receptor Farnesyl X Receptor (FXR) is a key target for treating chronic cholestatic and metabolic liver diseases, including non-alcoholic fatty liver disease (NAFLD).
  • FXR expression in the liver and intestine differentially impacts metabolic outcomes, but pan-FXR activation can lead to adverse effects like pruritus and altered lipid profiles.

Purpose of the Study:

  • To review the therapeutic potential of FXR activation, focusing on selective intestinal activation versus pan-FXR activation.
  • To discuss strategies for modulating FXR activation to mitigate side effects and explore the role of FXR antagonists in NAFLD.

Main Methods:

  • Review of molecular mechanisms underlying FXR activation.
  • Analysis of pre-clinical and clinical data from studies involving various steroidal and non-steroidal FXR agonists and antagonists.
  • Evaluation of strategies to restrict or modulate FXR activation.

Main Results:

  • Pre-clinical studies confirm FXR activation's efficacy in cholestatic and metabolic liver diseases.
  • The therapeutic advantage of selective intestinal FXR activation over pan-FXR activation remains under investigation.
  • FXR antagonists show potential as intestinal-selective agents in NAFLD models.

Conclusions:

  • FXR is a validated drug target for liver diseases, with ongoing research into optimizing its therapeutic application.
  • Selective modulation of FXR activity, particularly in the intestine, may offer a safer therapeutic window compared to broad activation.
  • Further research is needed to fully elucidate the benefits and risks of different FXR-targeting strategies in clinical settings.
Keywords:
AgonistsAntagonistsFXRNon-steroidal agonistsPartial agonistsSteroidal agonists

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