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Bile acids: natural ligands for an orphan nuclear receptor

D J Parks1, S G Blanchard, R K Bledsoe

  • 1Department of Molecular Biochemistry, Glaxo Wellcome Research and Development, Research Triangle Park NC, 27709, USA.

Science (New York, N.Y.)
|May 21, 1999
PubMed

Insights

Bile acids, like chenodeoxycholic acid, activate the farnesoid X receptor (FXR), a key regulator of cholesterol. This discovery reveals a nuclear bile acid signaling pathway impacting cholesterol homeostasis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Background:

  • Cholesterol homeostasis is tightly regulated by gene transcription.
  • The precise molecular mechanisms underlying bile acid-mediated gene regulation are not fully understood.
  • Bile acids are critical signaling molecules involved in various physiological processes.

Purpose of the Study:

  • To investigate the role of bile acids in regulating genes involved in cholesterol homeostasis.
  • To identify the specific bile acids that activate nuclear receptors.
  • To elucidate the molecular interactions between bile acids, nuclear receptors, and coactivators.

Main Methods:

  • Incubation of cells with physiological concentrations of various bile acids and their conjugates.
  • Activation assays for the farnesoid X receptor (FXR; NR1H4).
  • Analysis of the interaction between FXR and steroid receptor coactivator 1 (SRC-1) peptide in the presence of bile acids.

Main Results:

  • Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activated FXR.
  • Bile acids and their conjugates acted as ligands for FXR.
  • These bile acids modulated the interaction of FXR with a peptide derived from SRC-1.

Conclusions:

  • Evidence supports a nuclear bile acid signaling pathway.
  • This pathway may play a significant role in the regulation of cholesterol homeostasis.
  • FXR is a key mediator of bile acid signaling in cholesterol metabolism.

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