Vitamin D Receptor As an Intestinal Bile Acid Sensor

@article{Makishima2002VitaminDR,
  title={Vitamin D Receptor As an Intestinal Bile Acid Sensor},
  author={Makoto Makishima and Timothy T. Lu and Wen Xie and G. Kerr Whitfield and Hideharu Domoto and Ronald M. Evans and Mark R. Haussler and David J. Mangelsdorf},
  journal={Science},
  year={2002},
  volume={296},
  pages={1313 - 1316}
}
The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1α,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… 

Lithocholic Acid Is a Vitamin D Receptor Ligand That Acts Preferentially in the Ileum

The results indicate that LCA is a selective VDR ligand acting in the lower intestine, particularly the ileum, which may be a signaling molecule, which links intestinal bacteria and host VDR function.

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The endocrine vitamin D system in the gut

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Regulation of bile acid receptor activity☆

Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention.

Novel dietary ligands for VDR including curcumin, gamma-tocotrienol, and essential fatty acid derivatives that likely play a role in the bioactions of VDR are reported.

A novel bile acid-activated vitamin D receptor signaling in human hepatocytes.

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Structural determinants for vitamin D receptor response to endocrine and xenobiotic signals.

Comparative analysis of the VDR-LCA and V DR-1alpha,25(OH)2D3 structure-activity relationships should be useful in the development of bile acid-derived synthetic VDR ligands that selectively target VDR function in cancer and immune disorders without inducing adverse hypercalcemic effects.
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References

SHOWING 1-10 OF 36 REFERENCES

The Nuclear Vitamin D Receptor: Biological and Molecular Regulatory Properties Revealed

  • M. HausslerG. Whitfield P. Jurutka
  • Biology, Chemistry
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
  • 1998
The scope of this review will be limited to highlighting the actions of 1,25(OH)2D3 mediated by nuclear VDR and discussing new developments in the structure/function analysis of the receptor, including the phenotype of VDR knockout mice and the biochemical classification of patients with point mutations in the receptor.

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity

It is proposed that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid, and suggest that PxR agonists may prove useful in the treatment of human cholestatic liver disease.

Identification of a nuclear receptor for bile acids.

Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor, which demonstrates a mechanism by which bile acid transcriptionally regulate their biosynthesis and enterohepatic transport.

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

It is shown that activation of SXR/PXR is necessary and sufficient to both induce CYP3A enzymes and confer resistance to toxicity by LCA, as well as other xenotoxicants such as tribromoethanol and zoxazolamine.

Characterization of a vitamin D receptor knockout mouse as a model of colorectal hyperproliferation and DNA damage.

The sigmoid colon of VDR-KO mice, fed on an appropriate lactose/calcium-enriched diet to alleviate impaired calcium homeostasis-related phenotypic changes, is an excellent model for investigating induction and prevention of pre-malignant changes in one of the hotspots for human colorectal cancer incidence.

Transcriptional control of intestinal cytochrome P-4503A by 1alpha,25-dihydroxy vitamin D3.

The hypothesis that 1,25-D3 and VDR induce expression of intestinal CYP3A by binding of the activated VDR-RXR heterodimer to the CYP 3A PXR response element and promoting gene transcription is supported.

Nuclear receptors and lipid physiology: opening the X-files.

Some general principles that govern the actions of this class of bioactive lipids and their nuclear receptors are considered here, and the scheme that emerges reveals a complex molecular script at work.