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

doi:10.1126/science.1072891

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

Research output: Contribution to journal › Article › peer-review

451 Scopus citations

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 language	English (US)
Pages (from-to)	1703-1706
Number of pages	4
Journal	Science
Volume	296
Issue number	5573
DOIs	https://doi.org/10.1126/science.1072891
State	Published - May 31 2002

ASJC Scopus subject areas

General

Access to Document

10.1126/science.1072891

Cite this

@article{d13050b0f8584f9898aae47b5f5ba7b0,

title = "A natural product that lowers cholesterol as an antagonist ligand for FXR",

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.",

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

year = "2002",

month = may,

day = "31",

doi = "10.1126/science.1072891",

language = "English (US)",

volume = "296",

pages = "1703--1706",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "5573",

}

TY - JOUR

T1 - A natural product that lowers cholesterol as an antagonist ligand for FXR

AU - Urizar, Nancy L.

AU - Liverman, Amy B.

AU - Dodds, D'Nette T.

AU - Silva, Frank Valentin

AU - Ordentlich, Peter

AU - Yan, Yingzhuo

AU - Gonzalez, Frank J.

AU - Heyman, Richard A.

AU - Mangelsdorf, David J.

AU - Moore, David D.

PY - 2002/5/31

Y1 - 2002/5/31

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0037205046&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037205046&partnerID=8YFLogxK

U2 - 10.1126/science.1072891

DO - 10.1126/science.1072891

M3 - Article

C2 - 11988537

AN - SCOPUS:0037205046

SN - 0036-8075

VL - 296

SP - 1703

EP - 1706

JO - Science

JF - Science

IS - 5573

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this