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

Science  31 May 2002:
Vol. 296, Issue 5573, pp. 1703-1706
DOI: 10.1126/science.1072891

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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.

  • * To whom correspondence should be addressed. E-mail: moore{at}bcm.tmc.edu

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