Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
A Natural Product That Lowers Cholesterol As an Antagonist Ligand for FXR
Nancy L. Urizar,1Amy B. Liverman,2D'Nette T. Dodds,1Frank Valentin Silva,1Peter Ordentlich,3Yingzhuo Yan,3Frank J. Gonzalez,4Richard A. Heyman,3David J. Mangelsdorf,2David 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 guggulsteroneis 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-typemice fed a high-cholesterol diet but is not
effective in FXR-nullmice. Thus, we propose that inhibition of FXR
activation is thebasis for the cholesterol-lowering activity of
guggulsterone.Other natural products with specific biologic effects
may modulatethe activity of FXR or other relatively promiscuous
nuclear hormonereceptors.
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}bcm.tmc.edu
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 »
Causes and Metabolic Consequences of Fatty Liver.
N. Stefan, K. Kantartzis, and H.-U. Haring (2008)
Endocr. Rev.
29, 939-960
|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.
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 »
The Cholesterol-Raising Factor from Coffee Beans, Cafestol, as an Agonist Ligand for the Farnesoid and Pregnane X Receptors.
M.-L. Ricketts, M. V. Boekschoten, A. J. Kreeft, G. J. E. J. Hooiveld, C. J. A. Moen, M. Muller, R. R. Frants, S. Kasanmoentalib, S. M. Post, H. M. G. Princen, et al. (2007)
Mol. Endocrinol.
21, 1603-1616
|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 »
The Nuclear Hormone Receptor Farnesoid X Receptor (FXR) Is Activated by Androsterone.
S. Wang, K. Lai, F. J. Moy, A. Bhat, H. B. Hartman, and M. J. Evans (2006)
Endocrinology
147, 4025-4033
|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.
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 »
Integrating Complementary Medicine Into Cardiovascular Medicine: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents (Writing Committee to Develop an Expert Consensus Document on Complementary and Integrative Medicine).
J. H.K. Vogel, S. F. Bolling, R. B. Costello, E. M. Guarneri, M. W. Krucoff, J. C. Longhurst, B. Olshansky, K. R. Pelletier, C. M. Tracy, R. A. Vogel, et al. (2005)
J. Am. Coll. Cardiol.
46, 184-221
|Full Text »|PDF »
The Ratio of Constitutive Androstane Receptor to Pregnane X Receptor Determines the Activity of Guggulsterone against the Cyp2b10 Promoter.
Regulation of Carbohydrate Metabolism by the Farnesoid X Receptor.
K. R. Stayrook, K. S. Bramlett, R. S. Savkur, J. Ficorilli, T. Cook, M. E. Christe, L. F. Michael, and T. P. Burris (2005)
Endocrinology
146, 984-991
|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.
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 »
Guggulipid and Cholesterol Levels.
V. R. Karuparthy and S. Vepachedu (2003)
JAMA
290, 2800-2801
|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 »
Guggulipid for the Treatment of Hypercholesterolemia: A Randomized Controlled Trial.
P. O. Szapary, M. L. Wolfe, L. T. Bloedon, A. J. Cucchiara, A. H. DerMarderosian, M. D. Cirigliano, and D. J. Rader (2003)
JAMA
290, 765-772
|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 »
Transcription Profiling in Rat Liver in Response to Dietary Docosahexaenoic Acid Implicates Stearoyl-Coenzyme A Desaturase as a Nutritional Target for Lipid Lowering.
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 »
