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.

    • "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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    • "Source: University of California, Santa Cruz, genome browser. PGC-1β increase the expression of the fatty acid transporter, CD36, as well as many genes associated with fat oxidation in skeletal muscle [27] [30] [32] [33]. As creatine is also an important substrate for muscle energy homeostasis, we hypothesized that PGC-1α/ERRα or PGC- 1β/ERRα also regulates expression of the CrT, and therefore creatine uptake, in skeletal muscle. "
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    ABSTRACT: Intramuscular creatine plays a crucial role in maintaining skeletal muscle energy homeostasis, and its entry into the cell is dependent upon the sodium chloride dependent Creatine Transporter (CrT; Slc6a8). CrT activity is regulated by a number of factors including extra- and intracellular creatine concentrations, hormones, changes in sodium concentration, and kinase activity, however very little is known about the regulation of CrT gene expression. The present study aimed to investigate how Creatine Transporter (CrT) gene expression is regulated in skeletal muscle. Within the first intron of the CrT gene, we identified a conserved sequence that includes the motif recognized by the Estrogen-related receptor α (ERRα), also known as an Estrogen-related receptor response element (ERRE). Additional ERREs confirming to the known consensus sequence were also identified in the region upstream of the promoter. When partnered with peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α) or beta (PGC-1β), ERRα induces the expression of many genes important for cellular bioenergetics. We therefore hypothesized that PGC-1 and ERRα could also regulate CrT gene expression and creatine uptake in skeletal muscle. Here we show that adenoviral overexpression of PGC-1α or PGC-1β in L6 myotubes increased CrT mRNA (2.1 and 1.7-fold, P<0.0125) and creatine uptake (1.8 and 1.6-fold, P<0.0125), and this effect was inhibited with co-expression of shRNA for ERRα. Overexpression of a constitutively active ERRα (VP16-ERRα) increased CrT mRNA approximately 8-fold (P<0.05), resulting in a 2.2-fold (P<0.05) increase in creatine uptake. Lastly, chromatin immunoprecipitation assays revealed that PGC-1α and ERRα directly interact with the CrT gene and increase CrT gene expression.
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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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