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Science 17 May 2002:
Vol. 296. no. 5571, pp. 1313 - 1316
DOI: 10.1126/science.1070477
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Reports

Vitamin D Receptor As an Intestinal Bile Acid Sensor

Makoto Makishima,1* Timothy T. Lu,1 Wen Xie,2dagger G. Kerr Whitfield,3 Hideharu Domoto,1 Ronald M. Evans,2 Mark R. Haussler,3 David J. Mangelsdorf1ddagger

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.

1 Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9050, USA.
2 Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, Post Office Box 85800, San Diego, CA 92186-5800, USA.
3 Department of Biochemistry and Molecular Biophysics, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
*   Present address: Department of Organismal Biosystems, Osaka University, Suita, Osaka 565-0871, Japan.

dagger    Present address: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.

ddagger    To whom correspondence should be addressed. E-mail: davo.mango{at}utsouthwestern.edu

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J. Biol. Chem. 278, 38665-38674
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De-orphanization of Cytochrome P450 2R1: A MICROSOMAL VITAMIN D 25-HYDROXYLASE.
J. B. Cheng, D. L. Motola, D. J. Mangelsdorf, and D. W. Russell (2003)
J. Biol. Chem. 278, 38084-38093
   Abstract »    Full Text »    PDF »
Induction of Intestinal ATP-binding Cassette Transporters by a Phytosterol-derived Liver X Receptor Agonist.
E. Kaneko, M. Matsuda, Y. Yamada, Y. Tachibana, I. Shimomura, and M. Makishima (2003)
J. Biol. Chem. 278, 36091-36098
   Abstract »    Full Text »    PDF »
Previtamin D3 with a trans-Fused Decalin CD-ring Has Pronounced Genomic Activity.
L. Verlinden, A. Verstuyf, C. Verboven, G. Eelen, C. De Ranter, L.-J. Gao, Y.-J. Chen, I. Murad, M. Choi, K. Yamamoto, et al. (2003)
J. Biol. Chem. 278, 35476-35482
   Abstract »    Full Text »    PDF »
The first completed genome sequence from a teleost fish (Fugu rubripes) adds significant diversity to the nuclear receptor superfamily.
J. M. Maglich, J. A. Caravella, M. H. Lambert, T. M. Willson, J. T. Moore, and L. Ramamurthy (2003)
Nucleic Acids Res. 31, 4051-4058
   Abstract »    Full Text »    PDF »
Genetic Profiling Defines the Xenobiotic Gene Network Controlled by the Nuclear Receptor Pregnane X Receptor.
J. M. Rosenfeld, R. Vargas Jr., W. Xie, and R. M. Evans (2003)
Mol. Endocrinol. 17, 1268-1282
   Abstract »    Full Text »    PDF »
Cloning of a Functional Vitamin D Receptor from the Lamprey (Petromyzon marinus), an Ancient Vertebrate Lacking a Calcified Skeleton and Teeth.
G. K. Whitfield, H. T. L. Dang, S. F. Schluter, R. M. Bernstein, T. Bunag, L. A. Manzon, G. Hsieh, C. Encinas Dominguez, J. H. Youson, M. R. Haussler, et al. (2003)
Endocrinology 144, 2704-2716
   Abstract »    Full Text »    PDF »
Vitamin D receptor start codon polymorphism and colorectal cancer risk: effect modification by dietary calcium and fat in Singapore Chinese.
H.-L. Wong, A. Seow, K. Arakawa, H.-P. Lee, M. C. Yu, and S. A. Ingles (2003)
Carcinogenesis 24, 1091-1095
   Abstract »    Full Text »    PDF »
Syndecan-1 Expression Is Regulated in an Isoform-specific Manner by the Farnesoid-X Receptor.
A. M. Anisfeld, H. R. Kast-Woelbern, M. E. Meyer, S. A. Jones, Y. Zhang, K. J. Williams, T. Willson, and P. A. Edwards (2003)
J. Biol. Chem. 278, 20420-20428
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Protective Role of Hydroxysteroid Sulfotransferase in Lithocholic Acid-induced Liver Toxicity.
H. Kitada, M. Miyata, T. Nakamura, A. Tozawa, W. Honma, M. Shimada, K. Nagata, C. J. Sinal, G. L. Guo, F. J. Gonzalez, et al. (2003)
J. Biol. Chem. 278, 17838-17844
   Abstract »    Full Text »    PDF »
Vitamin D: More Than a "Bone-a-Fide" Hormone.
A. L. M. Sutton and P. N. MacDonald (2003)
Mol. Endocrinol. 17, 777-791
   Abstract »    Full Text »    PDF »
Bile Salt Transporters: Molecular Characterization, Function, and Regulation.
M. Trauner and J. L. Boyer (2003)
Physiol Rev 83, 633-671
   Abstract »    Full Text »    PDF »
Bile Acid Regulation of Hepatic Physiology: III. Bile acids and nuclear receptors.
J. Y. L. Chiang (2003)
Am J Physiol Gastrointest Liver Physiol 284, G349-G356
   Abstract »    Full Text »    PDF »
Identification of an endogenous ligand that activates pregnane X receptor-mediated sterol clearance.
I. Dussault, H.-D. Yoo, M. Lin, E. Wang, M. Fan, A. K. Batta, G. Salen, S. K. Erickson, and B. M. Forman (2003)
PNAS 100, 833-838
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Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor.
B. Goodwin, K. C. Gauthier, M. Umetani, M. A. Watson, M. I. Lochansky, J. L. Collins, E. Leitersdorf, D. J. Mangelsdorf, S. A. Kliewer, and J. J. Repa (2003)
PNAS 100, 223-228
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Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR).
J. Sonoda, W. Xie, J. M. Rosenfeld, J. L. Barwick, P. S. Guzelian, and R. M. Evans (2002)
PNAS 99, 13801-13806
   Abstract »    Full Text »    PDF »
Bile Acid Regulation of Gene Expression: Roles of Nuclear Hormone Receptors.
J. Y. L. Chiang (2002)
Endocr. Rev. 23, 443-463
   Abstract »    Full Text »    PDF »


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