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Science 296 (5573): 1703-1706

Copyright © 2002 by the American Association for the Advancement of Science

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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