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.


Logo for

PNAS 101 (24): 8912-8917

Copyright © 2004 by the National Academy of Sciences.


Regulation of PPAR{gamma} coactivator 1{alpha} (PGC-1{alpha}) signaling by an estrogen-related receptor {alpha} (ERR{alpha}) ligand

Patricia J. Willy *, {dagger}, Ian R. Murray *, Jing Qian *, Brett B. Busch {ddagger}, William C. Stevens, Jr. {ddagger}, Richard Martin {ddagger}, Raju Mohan {ddagger}, Sihong Zhou §, Peter Ordentlich §, Ping Wei §, Douglas W. Sapp §, Robert A. Horlick §, Richard A. Heyman *, and Ira G. Schulman *

Departments of *Biology, {ddagger}Chemistry, and §Lead Discovery, X-Ceptor Therapeutics, Inc., San Diego, CA 92121

Edited by Bruce M. Spiegelman, Harvard Medical School, Boston, MA, and approved May 10, 2004

Received for publication February 27, 2004.

Abstract: Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) coactivator 1{alpha} (PGC-1{alpha}) is a transcriptional coactivator that is a key component in the regulation of energy production and utilization in metabolic tissues. Recent work has identified PGC-1{alpha} as a strong coactivator of the orphan nuclear receptor estrogen-related receptor {alpha} (ERR{alpha}), implicating ERR{alpha} as a potential mediator of PGC-1{alpha} action. To understand the role of ERR{alpha} in PGC-1{alpha} signaling, a parallel approach of high-throughput screening and gene-expression analysis was used to identify ERR{alpha} small-molecule regulators and target genes. We report here the identification of a potent and selective ERR{alpha} inverse agonist that interferes effectively with PGC-1{alpha}/ERR{alpha}-dependent signaling. This inverse agonist inhibits the constitutive activity of ERR{alpha} in both biochemical and cell-based assays. Also, we demonstrate that monoamine oxidase B is an ERR{alpha} target gene whose expression is regulated by PGC-1{alpha} and ERR{alpha} and inhibited by the ERR{alpha} inverse agonist. The discovery of potent and selective ERR{alpha} modulators and their effect on PGC-1{alpha} signaling provides mechanistic insight into gene regulation by PGC-1{alpha}. These findings validate ERR{alpha} as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; AF2, activation function 2; DES, diethylstilbestrol; ER, estrogen receptor; ERR, estrogen-related receptor; FP, fluorescence polarization; MAOB, monoamine oxidase B; mSHP, mouse short heterodimer partner; OX/PHOS, oxidative phosphorylation; PGC-1{alpha}, PPAR{gamma} coactivator 1{alpha}; LBD, ligand-binding domain.

{dagger} To whom correspondence should be addressed at: Department of Biology, X-Ceptor Therapeutics, Inc., 4757 Nexus Center Drive, Suite 200, San Diego, CA 92121. E-mail: pwilly{at}

© 2004 by The National Academy of Sciences of the USA

Beneficial effects of resveratrol on respiratory chain defects in patients' fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling.
A. Lopes Costa, C. Le Bachelier, L. Mathieu, A. Rotig, A. Boneh, P. De Lonlay, M. A. Tarnopolsky, D. R. Thorburn, J. Bastin, and F. Djouadi (2014)
Hum. Mol. Genet. 23, 2106-2119
   Abstract »    Full Text »    PDF »
Bisphenol A modulates the metabolic regulator oestrogen-related receptor-{alpha} in T-cells.
R. Cipelli, L. Harries, K. Okuda, S. Yoshihara, D. Melzer, and T. Galloway (2014)
Reproduction 147, 419-426
   Abstract »    Full Text »    PDF »
The Corepressor NCoR1 Antagonizes PGC-1{alpha} and Estrogen-Related Receptor {alpha} in the Regulation of Skeletal Muscle Function and Oxidative Metabolism.
J. Perez-Schindler, S. Summermatter, S. Salatino, F. Zorzato, M. Beer, P. J. Balwierz, E. van Nimwegen, J. N. Feige, J. Auwerx, and C. Handschin (2012)
Mol. Cell. Biol. 32, 4913-4924
   Abstract »    Full Text »    PDF »
Molecular Pathways: The Metabolic Regulator Estrogen-Related Receptor {alpha} as a Therapeutic Target in Cancer.
C.-y. Chang and D. P. McDonnell (2012)
Clin. Cancer Res. 18, 6089-6095
   Abstract »    Full Text »    PDF »
Sustained expression of PGC-1{alpha} in the rat nigrostriatal system selectively impairs dopaminergic function.
C. Ciron, S. Lengacher, J. Dusonchet, P. Aebischer, and B. L. Schneider (2012)
Hum. Mol. Genet. 21, 1861-1876
   Abstract »    Full Text »    PDF »
Exercise training attenuates the hypermuscular phenotype and restores skeletal muscle function in the myostatin null mouse.
A. Matsakas, R. Macharia, A. Otto, M. I. Elashry, E. Mouisel, V. Romanello, R. Sartori, H. Amthor, M. Sandri, V. Narkar, et al. (2012)
Exp Physiol 97, 125-140
   Abstract »    Full Text »    PDF »
Dual Function of ERR{alpha} in Breast Cancer and Bone Metastasis Formation: Implication of VEGF and Osteoprotegerin.
A. Fradet, H. Sorel, L. Bouazza, D. Goehrig, B. Depalle, A. Bellahcene, V. Castronovo, H. Follet, F. Descotes, J. E. Aubin, et al. (2011)
Cancer Res. 71, 5728-5738
   Abstract »    Full Text »    PDF »
Estrogen-related receptor {alpha} regulates skeletal myocyte differentiation via modulation of the ERK MAP kinase pathway.
J. Murray and J. M. Huss (2011)
Am J Physiol Cell Physiol 301, C630-C645
   Abstract »    Full Text »    PDF »
Kinase Suppressor of Ras 1 (KSR1) Regulates PGC1{alpha} and Estrogen-Related Receptor {alpha} To Promote Oncogenic Ras-Dependent Anchorage-Independent Growth.
K. W. Fisher, B. Das, R. L. Kortum, O. V. Chaika, and R. E. Lewis (2011)
Mol. Cell. Biol. 31, 2453-2461
   Abstract »    Full Text »    PDF »
Estrogen-Related Receptor Gamma Promotes Mesenchymal-to-Epithelial Transition and Suppresses Breast Tumor Growth.
C. Tiraby, B. C. Hazen, M. L. Gantner, and A. Kralli (2011)
Cancer Res. 71, 2518-2528
   Abstract »    Full Text »    PDF »
Parkin degrades estrogen-related receptors to limit the expression of monoamine oxidases.
Y. Ren, H. Jiang, D. Ma, K. Nakaso, and J. Feng (2011)
Hum. Mol. Genet. 20, 1074-1083
   Abstract »    Full Text »    PDF »
PGC-1 Coactivators in Cardiac Development and Disease.
G. C. Rowe, A. Jiang, and Z. Arany (2010)
Circ. Res. 107, 825-838
   Abstract »    Full Text »    PDF »
Estrogen-related Receptor {gamma} Is a Key Regulator of Muscle Mitochondrial Activity and Oxidative Capacity.
S. M. Rangwala, X. Wang, J. A. Calvo, L. Lindsley, Y. Zhang, G. Deyneko, V. Beaulieu, J. Gao, G. Turner, and J. Markovits (2010)
J. Biol. Chem. 285, 22619-22629
   Abstract »    Full Text »    PDF »
PGC-1{alpha} coactivates estrogen-related receptor-{alpha} to induce the expression of glucokinase.
L. L. Zhu, Y. Liu, A. F. Cui, D. Shao, J. C. Liang, X. J. Liu, Y. Chen, N. Gupta, F. D. Fang, and Y. S. Chang (2010)
Am J Physiol Endocrinol Metab 298, E1210-E1218
   Abstract »    Full Text »    PDF »
Peroxisome Proliferator-Activated Receptor {gamma} Coactivator-1{alpha} Enhances Antiproliferative Activity of 5'-Deoxy-5-Fluorouridine in Cancer Cells through Induction of Uridine Phosphorylase.
X. Kong, H. Fan, X. Liu, R. Wang, J. Liang, N. Gupta, Y. Chen, F. Fang, and Y. Chang (2009)
Mol. Pharmacol. 76, 854-860
   Abstract »    Full Text »    PDF »
Modulating Estrogen Receptor-related Receptor-{alpha} Activity Inhibits Cell Proliferation.
S. Bianco, O. Lanvin, V. Tribollet, C. Macari, S. North, and J.-M. Vanacker (2009)
J. Biol. Chem. 284, 23286-23292
   Abstract »    Full Text »    PDF »
Inhibition of prostate cancer cell growth by second-site androgen receptor antagonists.
J. D. Joseph, B. M. Wittmann, M. A. Dwyer, H. Cui, D. A. Dye, D. P. McDonnell, and J. D. Norris (2009)
PNAS 106, 12178-12183
   Abstract »    Full Text »    PDF »
Estrogen-Related Receptor {alpha} Expression and Function Is Associated with the Transcriptional Coregulator AIB1 in Breast Carcinoma.
S. Heck, J. Rom, V. Thewes, N. Becker, B. Blume, H. P. Sinn, U. Deuschle, C. Sohn, A. Schneeweiss, and P. Lichter (2009)
Cancer Res. 69, 5186-5193
   Abstract »    Full Text »    PDF »
The orphan receptor ERR{alpha} interferes with steroid signaling.
C. Teyssier, S. Bianco, O. Lanvin, and J.-M. Vanacker (2008)
Nucleic Acids Res. 36, 5350-5361
   Abstract »    Full Text »    PDF »
Potentiation of ICI182,780 (Fulvestrant)-induced Estrogen Receptor-{alpha} Degradation by the Estrogen Receptor-related Receptor-{alpha} Inverse Agonist XCT790.
O. Lanvin, S. Bianco, N. Kersual, D. Chalbos, and J.-M. Vanacker (2007)
J. Biol. Chem. 282, 28328-28334
   Abstract »    Full Text »    PDF »
Crystal Structure of Human Estrogen-related Receptor {alpha} in Complex with a Synthetic Inverse Agonist Reveals Its Novel Molecular Mechanism.
J. Kallen, R. Lattmann, R. Beerli, A. Blechschmidt, M. J. J. Blommers, M. Geiser, J. Ottl, J.-M. Schlaeppi, A. Strauss, and B. Fournier (2007)
J. Biol. Chem. 282, 23231-23239
   Abstract »    Full Text »    PDF »
Orphan nuclear receptor estrogen-related receptor {alpha} is essential for adaptive thermogenesis.
J. A. Villena, M. B. Hock, W. Y. Chang, J. E. Barcas, V. Giguere, and A. Kralli (2007)
PNAS 104, 1418-1423
   Abstract »    Full Text »    PDF »
International Union of Pharmacology. LXVI. Orphan Nuclear Receptors.
G. Benoit, A. Cooney, V. Giguere, H. Ingraham, M. Lazar, G. Muscat, T. Perlmann, J.-P. Renaud, J. Schwabe, F. Sladek, et al. (2006)
Pharmacol. Rev. 58, 798-836
   Abstract »    Full Text »    PDF »
Estrogen-related receptor {alpha} as a therapeutic target in cancer.
R A Stein and D P McDonnell (2006)
Endocr. Relat. Cancer 13, S25-S32
   Abstract »    Full Text »    PDF »
RIP140 Expression Is Stimulated by Estrogen-related Receptor {alpha} during Adipogenesis.
D. Nichol, M. Christian, J. H. Steel, R. White, and M. G. Parker (2006)
J. Biol. Chem. 281, 32140-32147
   Abstract »    Full Text »    PDF »
Evidence for a Mitochondrial Regulatory Pathway Defined by Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator-1{alpha}, Estrogen-Related Receptor-{alpha}, and Mitofusin 2.
F. X. Soriano, M. Liesa, D. Bach, D. C. Chan, M. Palacin, and A. Zorzano (2006)
Diabetes 55, 1783-1791
   Abstract »    Full Text »    PDF »
Estrogen-related Receptor {alpha} Is a Repressor of Phosphoenolpyruvate Carboxykinase Gene Transcription.
B. Herzog, J. Cardenas, R. K. Hall, J. A. Villena, P. J. Budge, V. Giguere, D. K. Granner, and A. Kralli (2006)
J. Biol. Chem. 281, 99-106
   Abstract »    Full Text »    PDF »
PGC-1{alpha} Coactivates PDK4 Gene Expression via the Orphan Nuclear Receptor ERR{alpha}: a Mechanism for Transcriptional Control of Muscle Glucose Metabolism.
A. R. Wende, J. M. Huss, P. J. Schaeffer, V. Giguere, and D. P. Kelly (2005)
Mol. Cell. Biol. 25, 10684-10694
   Abstract »    Full Text »    PDF »
Identification of Neuronal Enhancers of the Proopiomelanocortin Gene by Transgenic Mouse Analysis and Phylogenetic Footprinting.
F. S. J. de Souza, A. M. Santangelo, V. Bumaschny, M. E. Avale, J. L. Smart, M. J. Low, and M. Rubinstein (2005)
Mol. Cell. Biol. 25, 3076-3086
   Abstract »    Full Text »    PDF »
Estrogen-related Receptor {alpha} (ERR{alpha}) Is a Transcriptional Regulator of Apolipoprotein A-IV and Controls Lipid Handling in the Intestine.
J. C. Carrier, G. Deblois, C. Champigny, E. Levy, and V. Giguere (2004)
J. Biol. Chem. 279, 52052-52058
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882