Bile acids are physiological ligands for a nuclear receptor

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• Bile acids are vital for dietary lipid absorption and cholesterol metabolism.
• The farnesoid X receptor (FXR) is an orphan nuclear receptor with unknown physiological ligands.
• Cholesterol 7 alpha-hydroxylase (CYP7A1) is the rate-limiting enzyme in bile acid synthesis.

Purpose of the Study:

• To identify physiological ligands for the farnesoid X receptor (FXR).
• To elucidate the regulatory role of bile acids in their own synthesis and transport.

Main Methods:

• In vitro assays to determine ligand binding to FXR.
• Gene expression analysis to assess transcriptional regulation.

Main Results:

• Bile acids were identified as physiological ligands for FXR.
• FXR activation by bile acids repressed the transcription of the cholesterol 7 alpha-hydroxylase gene.
• FXR activation by bile acids upregulated the intestinal bile acid-binding protein gene.

Conclusions:

• Bile acids serve as endogenous ligands for FXR, establishing a signaling pathway.
• This pathway demonstrates transcriptional control of bile acid biosynthesis via FXR.
• Bile acids also transcriptionally regulate their enterohepatic transport through FXR.