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Science 21 May 1999:
Vol. 284. no. 5418, pp. 1365 - 1368
DOI: 10.1126/science.284.5418.1365
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Reports

Bile Acids: Natural Ligands for an Orphan Nuclear Receptor

Derek J. Parks, 1 Steven G. Blanchard, 1 Randy K. Bledsoe, 2 Gyan Chandra, 3 Thomas G. Consler, 2 Steven A. Kliewer, 3 Julie B. Stimmel, 2 Timothy M. Willson, 4* Ann Marie Zavacki, 5 David D. Moore, 5 Jürgen M. Lehmann 3

Bile acids regulate the transcription of genes that control cholesterol homeostasis through molecular mechanisms that are poorly understood. Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activated the farnesoid X receptor (FXR; NR1H4), an orphan nuclear receptor. As ligands, these bile acids and their conjugates modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1. These results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis.

Departments of
1 Molecular Biochemistry,
2 Molecular Sciences,
3 Molecular Endocrinology,
4 Medicinal Chemistry, Glaxo Wellcome Research and Development, Research Triangle Park NC, 27709, USA.
5 Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.
*   To whom correspondence should be addressed. E-mail: tmw20653{at}glaxowellcome.com

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Protective Effects of 6-Ethyl Chenodeoxycholic Acid, a Farnesoid X Receptor Ligand, in Estrogen-Induced Cholestasis.
S. Fiorucci, C. Clerici, E. Antonelli, S. Orlandi, B. Goodwin, B. M. Sadeghpour, G. Sabatino, G. Russo, D. Castellani, T. M. Willson, et al. (2005)
J. Pharmacol. Exp. Ther. 313, 604-612
   Abstract »    Full Text »    PDF »
The Human Organic Anion Transporter 2 Gene Is Transactivated by Hepatocyte Nuclear Factor-4{alpha} and Suppressed by Bile Acids.
K. Popowski, J. J. Eloranta, M. Saborowski, M. Fried, P. J. Meier, and G. A. Kullak-Ublick (2005)
Mol. Pharmacol. 67, 1629-1638
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Regulation of Complement C3 Expression by the Bile Acid Receptor FXR.
J. Li, P. C. Pircher, I. G. Schulman, and S. K. Westin (2005)
J. Biol. Chem. 280, 7427-7434
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Interfacial properties of most monofluorinated bile acids deviate markedly from the natural congeners: studies with the Langmuir-Pockels surface balance.
J. M. Kauffman, R. Pellicciari, and M. C. Carey (2005)
J. Lipid Res. 46, 571-581
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Activation of the nuclear receptor FXR induces fibrinogen expression: a new role for bile acid signaling.
A. M. Anisfeld, H. R. Kast-Woelbern, H. Lee, Y. Zhang, F. Y. Lee, and P. A. Edwards (2005)
J. Lipid Res. 46, 458-468
   Abstract »    Full Text »    PDF »
Regulation of Carbohydrate Metabolism by the Farnesoid X Receptor.
K. R. Stayrook, K. S. Bramlett, R. S. Savkur, J. Ficorilli, T. Cook, M. E. Christe, L. F. Michael, and T. P. Burris (2005)
Endocrinology 146, 984-991
   Abstract »    Full Text »    PDF »
Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis.
A. Honda, G. Salen, Y. Matsuzaki, A. K. Batta, G. Xu, T. Hirayama, G. S. Tint, M. Doy, and S. Shefer (2005)
J. Lipid Res. 46, 287-296
   Abstract »    Full Text »    PDF »
Role of Farnesoid X Receptor in the Enhancement of Canalicular Bile Acid Output and Excretion of Unconjugated Bile Acids: A Mechanism for Protection against Cholic Acid-Induced Liver Toxicity.
M. Miyata, A. Tozawa, H. Otsuka, T. Nakamura, K. Nagata, F. J. Gonzalez, and Y. Yamazoe (2005)
J. Pharmacol. Exp. Ther. 312, 759-766
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Multiple mechanisms of ontogenic regulation of nuclear receptors during rat liver development.
N. Balasubramaniyan, M. Shahid, F. J. Suchy, and M. Ananthanarayanan (2005)
Am J Physiol Gastrointest Liver Physiol 288, G251-G260
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Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative.
R. Adachi, Y. Honma, H. Masuno, K. Kawana, I. Shimomura, S. Yamada, and M. Makishima (2005)
J. Lipid Res. 46, 46-57
   Abstract »    Full Text »    PDF »
FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade.
H. Li, F. Chen, Q. Shang, L. Pan, B. L. Shneider, J. Y. L. Chiang, B. M. Forman, M. Ananthanarayanan, G. S. Tint, G. Salen, et al. (2005)
Am J Physiol Gastrointest Liver Physiol 288, G60-G66
   Abstract »    Full Text »    PDF »
Ligand-Dependent Coactivation of the Human Bile Acid Receptor FXR by the Peroxisome Proliferator-Activated Receptor {gamma} Coactivator-1{alpha}.
R. S. Savkur, J. S. Thomas, K. S. Bramlett, Y. Gao, L. F. Michael, and T. P. Burris (2005)
J. Pharmacol. Exp. Ther. 312, 170-178
   Abstract »    Full Text »    PDF »
Presence of Diabetes-Inhibiting, Glutamic Acid Decarboxylase-Specific, IL-10-Dependent, Regulatory T Cells in Naive Nonobese Diabetic Mice.
S. You, C. Chen, W.-H. Lee, T. Brusko, M. Atkinson, and C.-P. Liu (2004)
J. Immunol. 173, 6777-6785
   Abstract »    Full Text »    PDF »
The Constitutive Androstane Receptor and Pregnane X Receptor Function Coordinately to Prevent Bile Acid-induced Hepatotoxicity.
J. Zhang, W. Huang, M. Qatanani, R. M. Evans, and D. D. Moore (2004)
J. Biol. Chem. 279, 49517-49522
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Farnesoid X receptor represses hepatic lipase gene expression.
A. Sirvent, A. J. M. Verhoeven, H. Jansen, V. Kosykh, R. J. Darteil, D. W. Hum, J.-C. Fruchart, and B. Staels (2004)
J. Lipid Res. 45, 2110-2115
   Abstract »    Full Text »    PDF »
Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1.
L. Alvarez, P. Jara, E. Sanchez-Sabate, L. Hierro, J. Larrauri, M. C. Diaz, C. Camarena, A. De la Vega, E. Frauca, E. Lopez-Collazo, et al. (2004)
Hum. Mol. Genet. 13, 2451-2460
   Abstract »    Full Text »    PDF »
Identification of Liver Receptor Homolog-1 as a Novel Regulator of Apolipoprotein AI Gene Transcription.
P. Delerive, C. M. Galardi, J. E. Bisi, E. Nicodeme, and B. Goodwin (2004)
Mol. Endocrinol. 18, 2378-2387
   Abstract »    Full Text »    PDF »


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