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Originally published in Science Express on 2 May 2002
Science 31 May 2002:
Vol. 296. no. 5573, pp. 1703 - 1706
DOI: 10.1126/science.1072891
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Reports

A Natural Product That Lowers Cholesterol As an Antagonist Ligand for FXR

Nancy L. Urizar,1 Amy B. Liverman,2 D'Nette T. Dodds,1 Frank Valentin Silva,1 Peter Ordentlich,3 Yingzhuo Yan,3 Frank J. Gonzalez,4 Richard A. Heyman,3 David J. Mangelsdorf,2 David D. Moore1*

Extracts of the resin of the guggul tree (Commiphora mukul) lower LDL (low-density lipoprotein) cholesterol levels in humans. The plant sterol guggulsterone [4,17(20)-pregnadiene-3,16-dione] is the active agent in this extract. We show that guggulsterone is a highly efficacious antagonist of the farnesoid X receptor (FXR), a nuclear hormone receptor that is activated by bile acids. Guggulsterone treatment decreases hepatic cholesterol in wild-type mice fed a high-cholesterol diet but is not effective in FXR-null mice. Thus, we propose that inhibition of FXR activation is the basis for the cholesterol-lowering activity of guggulsterone. Other natural products with specific biologic effects may modulate the activity of FXR or other relatively promiscuous nuclear hormone receptors.

1 Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
2 Howard Hughes Medical Institute, University of Texas - Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
3 X-Ceptor Therapeutics, Inc., 4757 Nexus Center Drive, San Diego, CA 92121, USA.
4 Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Building 37, Room 3E24, Bethesda, MD 20892, USA.
*   To whom correspondence should be addressed. E-mail: moore{at}bcm.tmc.edu

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   Abstract »    Full Text »    PDF »
Expression and activation of the farnesoid X receptor in the vasculature.
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Structure-activity relationship of bile acids and bile acid analogs in regard to FXR activation.
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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Identification of Gene-selective Modulators of the Bile Acid Receptor FXR.
I. Dussault, R. Beard, M. Lin, K. Hollister, J. Chen, J.-H. Xiao, R. Chandraratna, and B. M. Forman (2003)
J. Biol. Chem. 278, 7027-7033
   Abstract »    Full Text »    PDF »
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G. Lambert, M. J. A. Amar, G. Guo, H. B. Brewer Jr., F. J. Gonzalez, and C. J. Sinal (2003)
J. Biol. Chem. 278, 2563-2570
   Abstract »    Full Text »    PDF »
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J. A. Kramer, J. LeDeaux, D. Butteiger, T. Young, C. Crankshaw, H. Harlow, L. Kier, and B. G. Bhat (2003)
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