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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. Kelly^1*

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.

Present address: New York University Medical Center, New York, N.Y.

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