Estrogen-Related Receptor Directs Peroxisome Proliferator-Activated Receptor Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle

Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 11/2004; 24(20):9079-91. DOI: 10.1128/MCB.24.20.9079-9091.2004
Source: PubMed


Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERRalpha have not been well defined. To identify ERRalpha-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERRalpha. ERRalpha upregulated a subset of PGC-1alpha 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 ERRalpha-/- mice. Consistent with the gene expression results, ERRalpha increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERRalpha are known targets for the nuclear receptor PPARalpha, and therefore, the interaction between these regulatory pathways was explored. ERRalpha activated PPARalpha gene expression via direct binding of ERRalpha to the PPARalpha gene promoter. Furthermore, in fibroblasts null for PPARalpha and ERRalpha, the ability of ERRalpha to activate several PPARalpha targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1alpha was also shown to activate ERRalpha gene expression. We conclude that ERRalpha serves as a critical nodal point in the regulatory circuitry downstream of PGC-1alpha to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.

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Available from: Janice Huss, Nov 20, 2014
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    • "Both, in vivo and in vitro functional genomic analysis revealed ERRs as crucial regulators of mitochondrial biogenesis by promoting the transcription of genes involved in almost all aspects of mitochondrial function, including the genes encoding for components of the OxPhos system, the TCA cycle, fatty acid oxidation, mitochondrial dynamics, protein import and mtDNA replication and transcription [73- 75]. Furthermore, it has been shown that ERRs can regulate their own expression [76], in addition to the expression of GAPBα [77] and PPARα [78], resulting in a mechanism that amplifies the transcription of mitochondrial ERR target genes. The generation of knockout mouse models for specific ERR isoforms has confirmed the important role of ERRs in the regulation of mitochondrial biogenesis and function in vivo. "
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    Biochemical pharmacology 07/2015; 98(1). DOI:10.1016/j.bcp.2015.06.032 · 5.01 Impact Factor
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    • "We hypothesize that these TF mediate a highly inter-connected regulatory cascade including pathways such as HIF-1, AR, ER and Wnt/β-catenin that seem pivotal for lipid metabolism. The role of these pathways in the transcriptional regulation of lipid metabolism is a subject of intense studies [17,38,39,51-54]. A functional cooperation between the three TF in the modulation of these pathways is evident from our results and supported by literature evidence. "
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    • "The potential differential expression of these channels in our mice might explain our observations. Sex hormones have been shown to control enzymes implicated in sugar and fatty acid metabolism (Huss et al., 2004). We have seen that the abundance of key enzymes of the glycolytic pathway may be differently regulated in male and female eNOS −/− mice (Vignon-Zellweger et al., 2011). "
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