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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}

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C. Ramachandran, S. M. Nair, K.-W. Quirrin, and S. J. Melnick (2013)
Journal of Evidence-Based Complementary & Alternative Medicine 18, 248-256
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J. Pu, A. Yuan, P. Shan, E. Gao, X. Wang, Y. Wang, W. B. Lau, W. Koch, X.-L. Ma, and B. He (2013)
Eur. Heart J. 34, 1834-1845
   Abstract »    Full Text »    PDF »
Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease: Thematic Review Series: New Lipid and Lipoprotein Targets for the Treatment of Cardiometabolic Diseases.
G. Porez, J. Prawitt, B. Gross, and B. Staels (2012)
J. Lipid Res. 53, 1723-1737
   Abstract »    Full Text »    PDF »
Bile Acids Acutely Stimulate Insulin Secretion of Mouse {beta}-Cells via Farnesoid X Receptor Activation and KATP Channel Inhibition.
M. Dufer, K. Horth, R. Wagner, B. Schittenhelm, S. Prowald, T. F. J. Wagner, J. Oberwinkler, R. Lukowski, F. J. Gonzalez, P. Krippeit-Drews, et al. (2012)
Diabetes 61, 1479-1489
   Abstract »    Full Text »    PDF »
Hypolipidemic agent Z-guggulsterone: metabolism interplays with induction of carboxylesterase and bile salt export pump.
D. Yang, J. Yang, D. Shi, D. Xiao, Y.-T. Chen, C. Black, R. Deng, and B. Yan (2012)
J. Lipid Res. 53, 529-539
   Abstract »    Full Text »    PDF »
Reactive Oxygen Species-Dependent Apoptosis by Gugulipid Extract of Ayurvedic Medicine Plant Commiphora mukul in Human Prostate Cancer Cells Is Regulated by c-Jun N-Terminal Kinase.
D. Xiao, Y. Zeng, L. Prakash, V. Badmaev, M. Majeed, and S. V. Singh (2011)
Mol. Pharmacol. 79, 499-507
   Abstract »    Full Text »    PDF »
Prevention of Endotoxin-Induced Uveitis in Rats by Plant Sterol Guggulsterone.
N. M. Kalariya, M. Shoeb, A. B. M. Reddy, M. Zhang, F. J. G. M. van Kuijk, and K. V. Ramana (2010)
Invest. Ophthalmol. Vis. Sci. 51, 5105-5113
   Abstract »    Full Text »    PDF »
Retinoic acid represses CYP7A1 expression in human hepatocytes and HepG2 cells by FXR/RXR-dependent and independent mechanisms.
S.-Y. Cai, H. He, T. Nguyen, A. Mennone, and J. L. Boyer (2010)
J. Lipid Res. 51, 2265-2274
   Abstract »    Full Text »    PDF »
A Role of the Bile Salt Receptor FXR in Atherosclerosis.
J. Hageman, H. Herrema, A. K. Groen, and F. Kuipers (2010)
Arterioscler Thromb Vasc Biol 30, 1519-1528
   Abstract »    Full Text »    PDF »
Guggulsterone Suppresses Bile Acid-induced and Constitutive Caudal-related Homeobox 2 Expression in Gut-derived Adenocarcinoma Cells.
Anticancer Res 30, 1953-1960
   Abstract »    Full Text »    PDF »
Role of Cholesterol Pathways in Norovirus Replication.
K.-O. Chang (2009)
J. Virol. 83, 8587-8595
   Abstract »    Full Text »    PDF »
Bortezomib up-regulates activated signal transducer and activator of transcription-3 and synergizes with inhibitors of signal transducer and activator of transcription-3 to promote head and neck squamous cell carcinoma cell death.
C. Li, Y. Zang, M. Sen, R. J. Leeman-Neill, D. SK. Man, J. R. Grandis, and D. E. Johnson (2009)
Mol. Cancer Ther. 8, 2211-2220
   Abstract »    Full Text »    PDF »
A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia.
M. J. Evans, P. E. Mahaney, L. Borges-Marcucci, K. Lai, S. Wang, J. A. Krueger, S. J. Gardell, C. Huard, R. Martinez, G. P. Vlasuk, et al. (2009)
Am J Physiol Gastrointest Liver Physiol 296, G543-G552
   Abstract »    Full Text »    PDF »
Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation.
P. Lefebvre, B. Cariou, F. Lien, F. Kuipers, and B. Staels (2009)
Physiol Rev 89, 147-191
   Abstract »    Full Text »    PDF »
The p300 Acetylase Is Critical for Ligand-activated Farnesoid X Receptor (FXR) Induction of SHP.
S. Fang, S. Tsang, R. Jones, B. Ponugoti, H. Yoon, S.-Y. Wu, C.-M. Chiang, T. M. Willson, and J. K. Kemper (2008)
J. Biol. Chem. 283, 35086-35095
   Abstract »    Full Text »    PDF »
Transactivation of the Hepatitis B Virus Core Promoter by the Nuclear Receptor FXR{alpha}.
C. Ramiere, C. Scholtes, O. Diaz, V. Icard, L. Perrin-Cocon, M.-A. Trabaud, V. Lotteau, and P. Andre (2008)
J. Virol. 82, 10832-10840
   Abstract »    Full Text »    PDF »
Guggulsterone, a Farnesoid X Receptor Antagonist, Inhibits Constitutive and Inducible STAT3 Activation through Induction of a Protein Tyrosine Phosphatase SHP-1.
K. S. Ahn, G. Sethi, B. Sung, A. Goel, R. Ralhan, and B. B. Aggarwal (2008)
Cancer Res. 68, 4406-4415
   Abstract »    Full Text »    PDF »
z-Guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, inhibits angiogenesis in vitro and in vivo.
D. Xiao and S. V. Singh (2008)
Mol. Cancer Ther. 7, 171-180
   Abstract »    Full Text »    PDF »
Bile Acids Promote the Expression of Hepatitis C Virus in Replicon-Harboring Cells.
K.-O. Chang and D. W. George (2007)
J. Virol. 81, 9633-9640
   Abstract »    Full Text »    PDF »
Guggulsterone-Induced Apoptosis in Human Prostate Cancer Cells Is Caused by Reactive Oxygen Intermediate Dependent Activation of c-Jun NH2-Terminal Kinase.
S. V. Singh, S. Choi, Y. Zeng, E.-R. Hahm, and D. Xiao (2007)
Cancer Res. 67, 7439-7449
   Abstract »    Full Text »    PDF »
Expression of Human Nuclear Receptors in Plants for the Discovery of Plant-Derived Ligands.
E. V. Doukhanina, N. R. Apuya, H.-D. Yoo, C.-Y. Wu, P. Davidow, S. Krueger, R. B. Flavell, R. Hamilton, and S. C. Bobzin (2007)
J Biomol Screen 12, 385-395
   Abstract »    PDF »
The Hypolipidemic Agent Guggulsterone Regulates the Expression of Human Bile Salt Export Pump: Dominance of Transactivation over Farsenoid X Receptor-Mediated Antagonism.
R. Deng, D. Yang, A. Radke, J. Yang, and B. Yan (2007)
J. Pharmacol. Exp. Ther. 320, 1153-1162
   Abstract »    Full Text »    PDF »
Highly sensitive quantification of 7{alpha}-hydroxy-4-cholesten-3-one in human serum by LC-ESI-MS/MS.
A. Honda, K. Yamashita, M. Numazawa, T. Ikegami, M. Doy, Y. Matsuzaki, and H. Miyazaki (2007)
J. Lipid Res. 48, 458-464
   Abstract »    Full Text »    PDF »
International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor {alpha}, Farnesoid X Receptor beta, Liver X Receptor {alpha}, Liver X Receptor beta, and Vitamin D Receptor.
D. D. Moore, S. Kato, W. Xie, D. J. Mangelsdorf, D. R. Schmidt, R. Xiao, and S. A. Kliewer (2006)
Pharmacol. Rev. 58, 742-759
   Abstract »    Full Text »    PDF »
The Farnesoid X Receptor Promotes Adipocyte Differentiation and Regulates Adipose Cell Function in Vivo.
G. Rizzo, M. Disante, A. Mencarelli, B. Renga, A. Gioiello, R. Pellicciari, and S. Fiorucci (2006)
Mol. Pharmacol. 70, 1164-1173
   Abstract »    Full Text »    PDF »
Endocrine functions of bile acids.
S. M. Houten, M. Watanabe, and J. Auwerx (2006)
EMBO J. 25, 1419-1425
   Abstract »    Full Text »    PDF »
Guggulsterone Inhibits Osteoclastogenesis Induced by Receptor Activator of Nuclear Factor-{kappa}B Ligand and by Tumor Cells by Suppressing Nuclear Factor-{kappa}B Activation.
H. Ichikawa and B. B. Aggarwal (2006)
Clin. Cancer Res. 12, 662-668
   Abstract »    Full Text »    PDF »
Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice.
E. A. Hanniman, G. Lambert, T. C. McCarthy, and C. J. Sinal (2005)
J. Lipid Res. 46, 2595-2604
   Abstract »    Full Text »    PDF »
Guggulsterones induce apoptosis and differentiation in acute myeloid leukemia: identification of isomer-specific antileukemic activities of the pregnadienedione structure.
I. Samudio, M. Konopleva, S. Safe, T. McQueen, and M. Andreeff (2005)
Mol. Cancer Ther. 4, 1982-1992
   Abstract »    Full Text »    PDF »
Caspase-dependent apoptosis induction by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, in PC-3 human prostate cancer cells is mediated by Bax and Bak.
S. V. Singh, Y. Zeng, D. Xiao, V. G. Vogel, J. B. Nelson, R. Dhir, and Y. B. Tripathi (2005)
Mol. Cancer Ther. 4, 1747-1754
   Abstract »    Full Text »    PDF »
The Farnesoid X Receptor: A Molecular Link Between Bile Acid and Lipid and Glucose Metabolism.
T. Claudel, B. Staels, and F. Kuipers (2005)
Arterioscler Thromb Vasc Biol 25, 2020-2030
   Abstract »    Full Text »    PDF »
Guggulipid use in hyperlipidemia: Case report and review of the literature.
S. Sahni, C. A. Hepfinger, and K. A. Sauer (2005)
Am. J. Health Syst. Pharm. 62, 1690-1692
   Full Text »    PDF »
Bile acid signaling through FXR induces intracellular adhesion molecule-1 expression in mouse liver and human hepatocytes.
P. Qin, L. A. Borges-Marcucci, M. J. Evans, and D. C. Harnish (2005)
Am J Physiol Gastrointest Liver Physiol 289, G267-G273
   Abstract »    Full Text »    PDF »
The Ratio of Constitutive Androstane Receptor to Pregnane X Receptor Determines the Activity of Guggulsterone against the Cyp2b10 Promoter.
X. Ding and J. L. Staudinger (2005)
J. Pharmacol. Exp. Ther. 314, 120-127
   Abstract »    Full Text »    PDF »
The Hypolipidemic Natural Product Guggulsterone Is a Promiscuous Steroid Receptor Ligand.
T. P. Burris, C. Montrose, K. A. Houck, H. E. Osborne, W. P. Bocchinfuso, B. C. Yaden, C. C. Cheng, R. W. Zink, R. J. Barr, C. D. Hepler, et al. (2005)
Mol. Pharmacol. 67, 948-954
   Abstract »    Full Text »    PDF »
Ligand-Dependent Coactivation of the Human Bile Acid Receptor FXR by the Peroxisome Proliferator-Activated Receptor {gamma} Coactivator-1{alpha}.
R. S. Savkur, J. S. Thomas, K. S. Bramlett, Y. Gao, L. F. Michael, and T. P. Burris (2005)
J. Pharmacol. Exp. Ther. 312, 170-178
   Abstract »    Full Text »    PDF »
Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids.
B. Erranz, J. F. Miquel, W. S. Argraves, J. L. Barth, F. Pimentel, and M.-P. Marzolo (2004)
J. Lipid Res. 45, 2185-2198
   Abstract »    Full Text »    PDF »
Guggulsterone Inhibits NF-{kappa}B and I{kappa}B{alpha} Kinase Activation, Suppresses Expression of Anti-apoptotic Gene Products, and Enhances Apoptosis.
S. Shishodia and B. B. Aggarwal (2004)
J. Biol. Chem. 279, 47148-47158
   Abstract »    Full Text »    PDF »
Guggulsterone Activates Multiple Nuclear Receptors and Induces CYP3A Gene Expression through the Pregnane X Receptor.
D. E. Brobst, X. Ding, K. L. Creech, B. Goodwin, B. Kelley, and J. L. Staudinger (2004)
J. Pharmacol. Exp. Ther. 310, 528-535
   Abstract »    Full Text »    PDF »
Expression and activation of the farnesoid X receptor in the vasculature.
D. Bishop-Bailey, D. T. Walsh, and T. D. Warner (2004)
PNAS 101, 3668-3673
   Abstract »    Full Text »    PDF »
Structure-activity relationship of bile acids and bile acid analogs in regard to FXR activation.
T. Fujino, M. Une, T. Imanaka, K. Inoue, and T. Nishimaki-Mogami (2004)
J. Lipid Res. 45, 132-138
   Abstract »    Full Text »    PDF »
A Natural Product Ligand of the Oxysterol Receptor, Liver X Receptor.
K. S. Bramlett, K. A. Houck, K. M. Borchert, M. S. Dowless, P. Kulanthaivel, Y. Zhang, T. P. Beyer, R. Schmidt, J. S. Thomas, L. F. Michael, et al. (2003)
J. Pharmacol. Exp. Ther. 307, 291-296
   Abstract »    Full Text »    PDF »
Monitoring hepatic cholesterol 7{alpha}-hydroxylase activity by assay of the stable bile acid intermediate 7{alpha}-hydroxy-4-cholesten-3-one in peripheral blood.
C. Galman, I. Arvidsson, B. Angelin, and M. Rudling (2003)
J. Lipid Res. 44, 859-866
   Abstract »    Full Text »    PDF »
Guggulsterone Is a Farnesoid X Receptor Antagonist in Coactivator Association Assays but Acts to Enhance Transcription of Bile Salt Export Pump.
J. Cui, L. Huang, A. Zhao, J.-L. Lew, J. Yu, S. Sahoo, P. T. Meinke, I. Royo, F. Pelaez, and S. D. Wright (2003)
J. Biol. Chem. 278, 10214-10220
   Abstract »    Full Text »    PDF »
Bile Acid Regulation of Hepatic Physiology: III. Bile acids and nuclear receptors.
J. Y. L. Chiang (2003)
Am J Physiol Gastrointest Liver Physiol 284, G349-G356
   Abstract »    Full Text »    PDF »
Identification of Gene-selective Modulators of the Bile Acid Receptor FXR.
I. Dussault, R. Beard, M. Lin, K. Hollister, J. Chen, J.-H. Xiao, R. Chandraratna, and B. M. Forman (2003)
J. Biol. Chem. 278, 7027-7033
   Abstract »    Full Text »    PDF »
The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis.
G. Lambert, M. J. A. Amar, G. Guo, H. B. Brewer Jr., F. J. Gonzalez, and C. J. Sinal (2003)
J. Biol. Chem. 278, 2563-2570
   Abstract »    Full Text »    PDF »
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J. A. Kramer, J. LeDeaux, D. Butteiger, T. Young, C. Crankshaw, H. Harlow, L. Kier, and B. G. Bhat (2003)
J. Nutr. 133, 57-66
   Abstract »    Full Text »    PDF »

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