5Alpha-bile alcohols function as farnesoid X receptor antagonists

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids and alcohols.
• FXR regulates lipid homeostasis.
• FXR's unique binding orientation of bile acids, with the A ring facing helix 12, is crucial for coactivator recruitment.

Purpose of the Study:

• To investigate the role of the 5beta-configuration (cis-oriented A ring) of bile acids in FXR activation.
• To determine how this specific A-ring orientation influences FXR's function as a regulator of lipid homeostasis.

Main Methods:

• Synthesis and testing of bile alcohol isomers with 5beta-(A/B cis) and 5alpha-(A/B trans) configurations.
• Assessing FXR binding affinity for both isomers.
• Evaluating the ability of isomers to induce coactivator recruitment and FXR transactivation.

Main Results:

• 5beta-bile alcohols (5beta-cyprinol, bufol) are potent FXR agonists.
• 5alpha-bile alcohol counterparts antagonize FXR transactivation and target gene expression.
• Both isomers bind FXR, but their efficacy in coactivator recruitment and transactivation differs significantly based on A-ring orientation.

Conclusions:

• The A-ring orientation of bile salts is critical for determining FXR agonist or antagonist function.
• The 5beta-configuration is essential for potent FXR agonism.
• This finding highlights a key mechanism in bile acid-mediated regulation of lipid metabolism.