Vitamin D receptor as an intestinal bile acid sensor

Science. 2002 May 17;296(5571):1313-6. doi: 10.1126/science.1070477.

Abstract

The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We show that VDR also functions as a receptor for the secondary bile acid lithocholic acid (LCA), which is hepatotoxic and a potential enteric carcinogen. VDR is an order of magnitude more sensitive to LCA and its metabolites than are other nuclear receptors. Activation of VDR by LCA or vitamin D induced expression in vivo of CYP3A, a cytochrome P450 enzyme that detoxifies LCA in the liver and intestine. These studies offer a mechanism that may explain the proposed protective effects of vitamin D and its receptor against colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases*
  • Binding, Competitive
  • COS Cells
  • Cell Line
  • Colonic Neoplasms / prevention & control
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • DNA-Binding Proteins / metabolism
  • Dimerization
  • Gene Expression Regulation, Enzymologic
  • Histone Acetyltransferases
  • Humans
  • Intestine, Small / metabolism*
  • Ligands
  • Lithocholic Acid / analogs & derivatives
  • Lithocholic Acid / metabolism*
  • Lithocholic Acid / pharmacology
  • Male
  • Mice
  • Nuclear Receptor Coactivator 1
  • Oxidoreductases, N-Demethylating / genetics
  • Oxidoreductases, N-Demethylating / metabolism
  • Pregnane X Receptor
  • Promoter Regions, Genetic
  • Rats
  • Receptors, Calcitriol / agonists
  • Receptors, Calcitriol / genetics
  • Receptors, Calcitriol / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Steroid / metabolism
  • Transcription Factors / metabolism
  • Transfection

Substances

  • 3-ketolithocholic acid
  • DNA-Binding Proteins
  • Ligands
  • Pregnane X Receptor
  • Receptors, Calcitriol
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • Transcription Factors
  • farnesoid X-activated receptor
  • Lithocholic Acid
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • Cytochrome P-450 CYP3A
  • Oxidoreductases, N-Demethylating
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • Ncoa1 protein, mouse
  • Nuclear Receptor Coactivator 1