A natural product that lowers cholesterol as an antagonist ligand for FXR

Nancy L. Urizar, Amy B. Liverman, D'Nette T. Dodds, Frank Valentin Silva, Peter Ordentlich, Yingzhuo Yan, Frank J. Gonzalez, Richard A. Heyman, David J. Mangelsdorf, David D. Moore

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1703-1706
Number of pages4
JournalScience
Volume296
Issue number5573
DOIs
StatePublished - May 31 2002

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Urizar, N. L., Liverman, A. B., Dodds, DN. T., Silva, F. V., Ordentlich, P., Yan, Y., Gonzalez, F. J., Heyman, R. A., Mangelsdorf, D. J., & Moore, D. D. (2002). A natural product that lowers cholesterol as an antagonist ligand for FXR. Science, 296(5573), 1703-1706. https://doi.org/10.1126/science.1072891