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An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids

W Xie1, A Radominska-Pandya, Y Shi

  • 1Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.

Proceedings of the National Academy of Sciences of the United States of America
|March 15, 2001
PubMed

Insights

Steroid and xenobiotic receptor (SXR) and pregnane X receptor (PXR) are identified as bile acid receptors. These receptors are crucial for metabolizing toxic bile acids like lithocholic acid (LCA), preventing liver damage.

Area of Science:

  • Biochemistry
  • Hepatology
  • Pharmacology

Background:

  • Hepatic hydroxylation is vital for bile acid metabolism and excretion, preventing cholestasis and liver damage.
  • Bile acids, while essential, can be hepatotoxic if not properly metabolized.
  • The role of xenobiotic receptors in bile acid detoxification was previously unclear.

Purpose of the Study:

  • To investigate the role of the steroid and xenobiotic receptor (SXR) and pregnane X receptor (PXR) in bile acid metabolism.
  • To determine if SXR/PXR can function as bile acid receptors.
  • To elucidate the involvement of SXR/PXR in the detoxification of toxic bile acids.

Main Methods:

  • Utilized cultured cells and animal models, including knockout and transgenic mice.
  • Investigated the interaction of lithocholic acid (LCA) with SXR/PXR.
  • Assessed the induction of CYP3A enzymes and resistance to xenotoxicants.

Main Results:

  • Demonstrated that SXR/PXR function as bile acid receptors in both cellular and animal models.
  • Identified lithocholic acid (LCA) as a metabolic substrate for CYP3A hydroxylation, mediated by SXR/PXR.
  • Showed that SXR/PXR activation is necessary and sufficient to induce CYP3A enzymes and confer resistance to LCA toxicity.

Conclusions:

  • Established SXR and PXR as functional bile acid receptors.
  • Highlighted the critical role of the xenobiotic response pathway in the detoxification of bile acids.
  • Provided evidence for SXR/PXR's protective role against bile acid-induced liver injury.

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