Submitted to: Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/23/2002
Publication Date: 5/31/2002
Citation: Urizar, N.L., Liverman, A.B., Dodds, D.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. Interpretive Summary: This paper studied guggulsterone, a natural botanical product that has been shown in studies in India to lower cholesterol and triglycerides in humans. By comparing normal mice and mice deficient in FXR, we found that guggulsterone blocks the effects of FXR. FXR is an important regulator of cholesterol metabolism and is likely to be the target for beneficial effects of guggulsterone.
Technical 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.