Related Experiment Video

Updated: Oct 2, 2025

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

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NRF2 Activation in Autophagy Defects Suppresses a Pharmacological Transactivation of the Nuclear Receptor FXR

Eun Young Kim1, Jae Man Lee1,2

  • 1Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Korea.

Antioxidants (Basel, Switzerland)
|February 25, 2022
PubMed

Insights

Autophagy defects activate NF-E2-related factor 2 (NRF2), which inhibits the Farnesoid X Receptor (FXR). This discovery reveals a new regulatory pathway impacting metabolic diseases and FXR-targeted therapies.

Area of Science:

  • Cellular Biology
  • Metabolic Regulation
  • Molecular Mechanisms

Background:

  • NF-E2-related factor 2 (NRF2) is an antioxidant transcription factor activated by autophagy defects.
  • Farnesoid X Receptor (FXR) regulates bile acid synthesis, enterohepatic circulation, and glucose/lipid metabolism.
  • FXR agonists like obeticholic acid are used for liver diseases.

Purpose of the Study:

  • To investigate the interaction between NRF2 activation and FXR transactivation.
  • To elucidate the role of the autophagy-NRF2 axis in regulating FXR activity.
  • To explore potential therapeutic implications for metabolic diseases.

Main Methods:

  • Utilized liver-specific *Atg7* knockout mice and autophagy inhibitors.
  • Administered small molecules to induce NRF2 activation in cultured cells.
  • Tested the effect of the antioxidant butylated hydroxyanisole on FXR activation in vivo.

Main Results:

  • Autophagy deficiency led to NRF2 activation and impaired FXR target gene induction.
  • Enforced NRF2 activation suppressed pharmacological FXR activation in cells and *in vivo*.
  • NRF2 activation by butylated hydroxyanisole inhibited FXR activation.

Conclusions:

  • The basal autophagy-NRF2 axis is a novel regulator of FXR transactivation.
  • NRF2 activation impedes FXR-mediated metabolic regulation.
  • Findings suggest new therapeutic strategies for metabolic diseases targeting the autophagy-NRF2-FXR pathway.
Keywords:
FXRautophagykeap1ligandnrf2nuclear receptortransactivation

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