Molecular and Cellular Biology, October 2004, p. 9079-9091, Vol. 24, No. 20
0270-7306/04/$08.00+0 DOI: 10.1128/MCB.24.20.9079-9091.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Estrogen-Related Receptor
Directs Peroxisome Proliferator-Activated Receptor
Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle
Janice M. Huss,1 Inés Pineda Torra,2,
Bart Staels,2 Vincent Giguère,3 and Daniel P. Kelly1*
Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri,1
Départment d' Athérosclérose, Institut Pasteur de Lille, Université de Lille II, Lille, France,2
Molecular Oncology, McGill University Health Centre, Montreal, Quebec, Canada3
Received 26 February 2004/
Returned for modification 23 April 2004/
Accepted 26 July 2004
Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor
(PPAR
) coactivator 1
(PGC-1
), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERR
have not been well defined. To identify ERR
-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERR
. ERR
upregulated a subset of PGC-1
target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C2C12 myotubes, and cardiac and skeletal muscle of ERR
/ mice. Consistent with the gene expression results, ERR
increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERR
are known targets for the nuclear receptor PPAR
, and therefore, the interaction between these regulatory pathways was explored. ERR
activated PPAR
gene expression via direct binding of ERR
to the PPAR
gene promoter. Furthermore, in fibroblasts null for PPAR
and ERR
, the ability of ERR
to activate several PPAR
targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1
was also shown to activate ERR
gene expression. We conclude that ERR
serves as a critical nodal point in the regulatory circuitry downstream of PGC-1
to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.
* Corresponding author. Mailing address: Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110. Phone: (314) 362-8908. Fax: (314) 362-0186. E-mail: dkelly{at}im.wustl.edu.
Present address: New York University Medical Center, New York, N.Y.
Molecular and Cellular Biology, October 2004, p. 9079-9091, Vol. 24, No. 20
0022-538X/04/$08.00+0 DOI: 10.1128/MCB.24.20.9079-9091.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
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Copyright © 2004 by the American Society for Microbiology. All rights reserved.