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Structure-activity relationship of bile acids and bile acid analogs in regard to FXR activation

Tomofumi Fujino1, Mizuho Une, Tsuneo Imanaka

  • 1Division of Biosignaling, National Institute of Health Sciences, Tokyo, Japan.

Journal of Lipid Research
|September 18, 2003
PubMed

Insights

Altering bile acid structures, particularly adding bulky groups at the beta-position, significantly impacts their ability to activate the farnesoid X receptor (FXR). These findings are crucial for understanding FXR ligand structure-activity relationships in metabolism.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Background:

  • The farnesoid X receptor (FXR) is a nuclear receptor critical for regulating bile acid and cholesterol metabolism.
  • Understanding the structure-activity relationships of FXR ligands is essential for developing therapeutic agents.

Purpose of the Study:

  • To investigate the functional roles of structural elements in natural bile acids and their derivatives concerning FXR activation.
  • To elucidate how modifications like hydroxyl group epimerization and alkyl substitutions affect FXR ligand binding and activation.

Main Methods:

  • Utilized a cell-based FXR response element-driven luciferase assay to measure FXR activation.
  • Employed an in vitro coactivator association assay to assess ligand-receptor interactions.
  • Synthesized and tested various modified bile acids, including epimers and alkylated derivatives.

Main Results:

  • Conversion of carboxyl groups to alcohols in chenodeoxycholic acid (CDCA) and cholic acid (CA) minimally affected FXR activation.
  • 7beta-epimers of bile alcohols and hydroxyl epimers of deoxycholic acid (DCA) showed significantly reduced or inactive FXR-binding capacity.
  • Introduction of alkyl groups at the 7beta- or 3beta-positions of CDCA diminished FXR activation, with bulkier substituents causing greater reduction.

Conclusions:

  • The 7beta-hydroxyl group and beta-oriented hydroxyl groups at positions 3 or 12 negatively impact FXR activation.
  • Bulky substituents, including hydroxyl groups and alkyl residues, at the beta-position of cholanoids decrease their efficacy in activating the farnesoid X receptor.

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