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: 5.04). 11/2004; 24(20):9079-91. DOI: 10.1128/MCB.24.20.9079-9091.2004
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Janice Huss, Nov 20, 2014
  • Source
    • "ERRs and PGC-1s also coordinately control OXPHOS pathway by regulating the transcription of SODs genes (Christoph et al., 2003; Huss et al., 2004; Mootha et al., 2004; Schreiber et al., 2003, 2004). Like the effects of kaempferol on TFAM and Mfn2 expression, kaempferol decreased Mn-SOD and Cu/Zn-SOD gene expression in the three cell lines (Figures 2B, 2E and 2H). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Kaempferol is a dietary flavonoid that is thought to function as a selective estrogen receptor modulator. Estrogen-related receptors alpha and gamma (ERRα and ERRγ) are orphan nuclear receptors that play important roles in mitochondrial biogenesis and cancer development. In the present study, we demonstrated that Kaempferol could functionally antagonize the activities of ERRs based on both response element reporter systems and target gene analysis. We also further confirmed that kaempferol modulated mitochondrial function and suppressed cancer cell growth. These evidences collectively suggest that kaempferol may exert their anti-cancer activities through antagonizing ERRs activities.
    Cell Biology International 08/2013; 37(11). DOI:10.1002/cbin.10152 · 1.64 Impact Factor
  • Source
    • "However, a marked depletion in ERRa was observed in all cell lines after exposure to the potent ERRa-specific inverse agonist XCT790. These results, which suggest a model for cell-type-specific control of ERRa stability by biarylpyrazole compounds, are supported by findings in ERRa knockout mice, wherein gene induction was strongly dependent on the tissue type (Huss et al., 2004). Alternatively, the selective reduction of ERRa levels in different cell types might fine-tune ERRa signaling, for example, to modulate osteoblastic and adipogenic programs (Ijichi et al., 2007; Delhon et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The orphan nuclear receptor estrogen-related receptor alpha (ERRα) directs the transcription of nuclear genes involved in energy homeostasis control and the regulation of mitochondrial mass and function. A crucial role for controlling ERRα-mediated target gene expression has been ascribed to the biarylpyrazole compound, AM251, through direct binding to and destabilization of ERRα protein. Here, we provide evidence that structurally-related AM251 analogs also have negative impacts on ERRα protein levels in a cell type-dependent manner, while having no deleterious actions on ERRγ. We show that these off-target cellular effects of AM251 are mediated by proteasomal degradation of nuclear ERRα. Cell treatment with the nuclear export inhibitor, leptomycin B, did not prevent AM251-induced destabilization of ERRα protein, whereas proteasome inhibition with MG132 stabilized and maintained its DNA-binding function, indicative of ERRα being a target of nuclear proteasomal complexes. NativePAGE analysis revealed that ERRα formed a -220 kDa multiprotein nuclear complex that was devoid of ERRγ and the coregulator peroxisome proliferator-activated receptor α coactivator-1. AM251 induced SUMO-2,3 incorporation in ERRα in conjunction with increased protein kinase C activity, whose activation by phorbol ester also promoted ERRα protein loss. Downregulation of ERRα by AM251 or small interfering RNA led to increased mitochondria biogenesis while negatively impacting mitochondrial membrane potential. These results reveal a novel molecular mechanism by which AM251 and related compounds alter mitochondrial physiology through destabilization of ERRα.
    Molecular pharmacology 10/2012; 83(1). DOI:10.1124/mol.112.082651 · 4.12 Impact Factor
  • Source
    • "ERRa is localized predominantly in cell nuclei and is most highly expressed in skeletal muscle, kidney, heart, brain, and intestine [1] [7] [11]. Recent studies have demonstrated that ERRa regulates transcription of genes involved in metabolism [12] [13] [14] [15] [16]. Elevated ERRa protein levels have been associated with certain breast, endometrial, ovarian, prostate, and colorectal cancers [17] [18] [19] [20] [21] [22] [23] [24] [25] [26], but its exact role in cancer progression is not clear. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Estrogen-related receptor alpha (ERRα) is an orphan nuclear receptor whose elevated expression is thought to contribute to breast, colon, and ovarian cancers. In order to investigate the role of ERRα in human disease, there is a need for immunological reagents suitable for detection and purification of ERRα. We expressed recombinant human ERRα in Escherichia coli, purified the protein, and used it to generate monoclonal antibodies (mAbs) to ERRα. Nine high-affinity mAbs were chosen for their abilities to detect overexpressed ERRα in enzyme-linked immunosorbent assays (ELISAs) and Western blots, after which isotyping and preliminary epitope mapping was performed. The mAbs were all IgG subtypes and reacted with several different regions of full-length ERRα. A majority of the mAbs were found to be useful for immunoprecipitation of ERRα, and several could detect DNA-bound ERRα in electrophoretic mobility supershift assays (EMSAs) and chromatin immunoprecipitation (ChIP). The suitability of mAbs to detect ERRα in immunofluorescence assays was assessed. One mAb in particular, 2ERR10, could specifically detect endogenous ERRα in mammary carcinoma cells. Finally, we performed assays to screen for mAbs that gently release ERRα in the presence of a low-molecular-weight polyhydroxylated compound (polyol) and nonchaotropic salt. Using gentle immunoaffinity chromatography, we were able to isolate ERRα from mammalian cells by eluting with a polyol-salt solution. Our characterization studies show that these monoclonal antibodies perform well in a variety of biochemical assays. We anticipate that these novel reagents will prove useful for the detection and purification of ERRα in research and clinical applications.
    Protein Expression and Purification 05/2012; 84(1):47-58. DOI:10.1016/j.pep.2012.04.020 · 1.51 Impact Factor
Show more