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PMID: 18778951 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

ERRalpha: a metabolic function for the oldest orphan.

Trends in endocrinology and metabolism: TEM ·Vol. 19 ·No. 8 ·2008-10-00 ·Pages 269-76

Villena JA, Kralli A

Abstract

Estrogen receptor related receptor (ERR)alpha was one of the first identified (1988) orphan nuclear receptors. Many of the orphan receptors identified after ERRalpha were deorphanized in a timely manner and appreciated as key transcriptional regulators of metabolic pathways. ERRalpha, however, remains an orphan. Nevertheless, recent studies have defined regulatory mechanisms and transcriptional targets of ERRalpha, allowing this receptor to join ranks with other nuclear receptors that control metabolism. Notably, mice lacking ERRalpha show defects when challenged with stressors that require a 'shift of gears' in energy metabolism, such as exposure to cold, cardiac overload or infection. These findings establish the importance of ERRalpha for adaptive energy metabolism, and suggest that strategies targeting ERRalpha may be useful in fighting metabolic diseases.

MeSH Terms
Animals Energy Metabolism/genetics,physiology Humans Metabolic Networks and Pathways/genetics,physiology Mice Mice, Knockout Models, Biological Multigene Family Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Receptors, Estrogen/genetics,physiology Trans-Activators/physiology Transcription Factors
Chemicals
ERRalpha estrogen-related receptor Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Ppargc1a protein, mouse Receptors, Estrogen Trans-Activators Transcription Factors
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Villena Josep A
Institut de Recerca Hospital Universitari Vall d'Hebron, Grup de Metabolisme i Obesitat, Barcelona, Spain.
Kralli Anastasia
References (66)
66 references, click to expand
  1. Studying non-mammalian models? Not a fool's ERRand!
    Trends Endocrinol Metab. 2006 May-Jun;17(4):166-71 PMID: 16580224
  2. Suppression of oxidative metabolism and mitochondrial biogenesis by the transcriptional corepressor RIP140 in mouse adipocytes.
    J Clin Invest. 2006 Jan;116(1):125-36 PMID: 16374519
  3. Phosphorylation-dependent sumoylation regulates estrogen-related receptor-alpha and -gamma transcriptional activity through a synergy control motif.
    Mol Endocrinol. 2008 Mar;22(3):570-84 PMID: 18063693
  4. Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2.
    Diabetes. 2006 Jun;55(6):1783-91 PMID: 16731843
  5. On the intractability of estrogen-related receptor alpha as a target for activation by small molecules.
    J Med Chem. 2007 Dec 27;50(26):6722-4 PMID: 18052088
  6. Regulation of PPARgamma coactivator 1alpha (PGC-1alpha) signaling by an estrogen-related receptor alpha (ERRalpha) ligand.
    Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8912-7 PMID: 15184675
  7. Identification of a specific molecular repressor of the peroxisome proliferator-activated receptor gamma Coactivator-1 alpha (PGC-1alpha).
    J Biol Chem. 2002 Dec 27;277(52):50991-5 PMID: 12397057
  8. Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle.
    Mol Cell Biol. 2004 Oct;24(20):9079-91 PMID: 15456881
  9. Mitofusins 1/2 and ERRalpha expression are increased in human skeletal muscle after physical exercise.
    J Physiol. 2005 Aug 15;567(Pt 1):349-58 PMID: 15961417
  10. Identification of ERRalpha as a specific partner of PGC-1alpha for the activation of PDK4 gene expression in muscle.
    FEBS J. 2006 Apr;273(8):1669-80 PMID: 16623704
  11. Estrogen-related receptor alpha as a therapeutic target in cancer.
    Endocr Relat Cancer. 2006 Dec;13 Suppl 1:S25-32 PMID: 17259555
  12. Estrogen-related receptor alpha modulates the expression of adipogenesis-related genes during adipocyte differentiation.
    Biochem Biophys Res Commun. 2007 Jul 6;358(3):813-8 PMID: 17512501
  13. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1.
    Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8466-71 PMID: 12832613
  14. The nuclear receptor superfamily: the second decade.
    Cell. 1995 Dec 15;83(6):835-9 PMID: 8521507
  15. Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism.
    Endocr Rev. 2006 Dec;27(7):728-35 PMID: 17018837
  16. Epidermal growth factor-induced signaling in breast cancer cells results in selective target gene activation by orphan nuclear receptor estrogen-related receptor alpha.
    Cancer Res. 2005 Jul 15;65(14):6120-9 PMID: 16024613
  17. The nuclear receptor ERRalpha is required for the bioenergetic and functional adaptation to cardiac pressure overload.
    Cell Metab. 2007 Jul;6(1):25-37 PMID: 17618854
  18. Estrogen-related receptor alpha is essential for the expression of antioxidant protection genes and mitochondrial function.
    Biochem Biophys Res Commun. 2007 May 25;357(1):231-6 PMID: 17418099
  19. The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis.
    Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6472-7 PMID: 15087503
  20. Estrogen-related receptor alpha (ERRalpha) is a transcriptional regulator of apolipoprotein A-IV and controls lipid handling in the intestine.
    J Biol Chem. 2004 Dec 10;279(50):52052-8 PMID: 15466464
  21. The orphan nuclear receptor estrogen-related receptor alpha is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene.
    Mol Cell Biol. 1997 Sep;17(9):5400-9 PMID: 9271417
  22. The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor alpha (ERRalpha).
    J Biol Chem. 2003 Mar 14;278(11):9013-8 PMID: 12522104
  23. Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense.
    Genes Dev. 2007 Aug 1;21(15):1909-20 PMID: 17671090
  24. Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3.
    Mol Cell. 2002 Feb;9(2):303-13 PMID: 11864604
  25. Nuclear receptors and lipid physiology: opening the X-files.
    Science. 2001 Nov 30;294(5548):1866-70 PMID: 11729302
  26. Estrogen-related receptors stimulate pyruvate dehydrogenase kinase isoform 4 gene expression.
    J Biol Chem. 2006 Dec 29;281(52):39897-906 PMID: 17079227
  27. Phosphorylation-dependent sumoylation of estrogen-related receptor alpha1.
    Biochemistry. 2007 Aug 28;46(34):9795-804 PMID: 17676930
  28. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes.
    Mol Cell Biol. 2000 Mar;20(5):1868-76 PMID: 10669761
  29. A single nucleotide in an estrogen-related receptor alpha site can dictate mode of binding and peroxisome proliferator-activated receptor gamma coactivator 1alpha activation of target promoters.
    Mol Endocrinol. 2006 Feb;20(2):302-10 PMID: 16150865
  30. Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha.
    J Med Chem. 2004 Nov 4;47(23):5593-6 PMID: 15509154
  31. Metabolic regulation by the nuclear receptor corepressor RIP140.
    Trends Endocrinol Metab. 2006 Aug;17(6):243-50 PMID: 16815031
  32. To ERR in the estrogen pathway.
    Trends Endocrinol Metab. 2002 Jul;13(5):220-5 PMID: 12185669
  33. Mitochondria: dynamic organelles in disease, aging, and development.
    Cell. 2006 Jun 30;125(7):1241-52 PMID: 16814712
  34. Estrogen-related receptors as emerging targets in cancer and metabolic disorders.
    Curr Top Med Chem. 2006;6(3):203-15 PMID: 16515477
  35. Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma.
    Cell Metab. 2007 May;5(5):345-56 PMID: 17488637
  36. Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha.
    Mol Cell Biol. 2003 Nov;23(22):7947-56 PMID: 14585956
  37. Estrogen-related receptor alpha1 transcriptional activities are regulated in part via the ErbB2/HER2 signaling pathway.
    Mol Cancer Res. 2007 Jan;5(1):71-85 PMID: 17259347
  38. Identification of a new class of steroid hormone receptors.
    Nature. 1988 Jan 7;331(6151):91-4 PMID: 3267207
  39. Estrogen-related receptor alpha 1 functionally binds as a monomer to extended half-site sequences including ones contained within estrogen-response elements.
    Mol Endocrinol. 1997 Mar;11(3):342-52 PMID: 9058380
  40. Receptor-selective coactivators as tools to define the biology of specific receptor-coactivator pairs.
    Mol Cell. 2006 Dec 8;24(5):797-803 PMID: 17157261
  41. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.
    Nat Genet. 2003 Jul;34(3):267-73 PMID: 12808457
  42. A polymorphic autoregulatory hormone response element in the human estrogen-related receptor alpha (ERRalpha) promoter dictates peroxisome proliferator-activated receptor gamma coactivator-1alpha control of ERRalpha expression.
    J Biol Chem. 2004 Apr 30;279(18):18504-10 PMID: 14978033
  43. A role for estrogen-related receptor alpha in the control of mitochondrial fatty acid beta-oxidation during brown adipocyte differentiation.
    J Biol Chem. 1997 Dec 12;272(50):31693-9 PMID: 9395511
  44. The PGC-1-related protein PERC is a selective coactivator of estrogen receptor alpha.
    J Biol Chem. 2002 Apr 19;277(16):13918-25 PMID: 11854298
  45. Orphan nuclear receptor estrogen-related receptor alpha is essential for adaptive thermogenesis.
    Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1418-23 PMID: 17229846
  46. PGC-1 coactivators: inducible regulators of energy metabolism in health and disease.
    J Clin Invest. 2006 Mar;116(3):615-22 PMID: 16511594
  47. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases.
    Nature. 2006 Oct 19;443(7113):787-95 PMID: 17051205
  48. Crystal structure of human estrogen-related receptor alpha in complex with a synthetic inverse agonist reveals its novel molecular mechanism.
    J Biol Chem. 2007 Aug 10;282(32):23231-9 PMID: 17556356
  49. Estrogen receptor-related receptor alpha: a mediator of estrogen response in bone.
    J Clin Endocrinol Metab. 2005 May;90(5):3115-21 PMID: 15713703
  50. PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity.
    Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12378-83 PMID: 14530391
  51. Estrogen-related receptor alpha is a repressor of phosphoenolpyruvate carboxykinase gene transcription.
    J Biol Chem. 2006 Jan 6;281(1):99-106 PMID: 16267049
  52. Definition of the molecular basis for estrogen receptor-related receptor-alpha-cofactor interactions.
    Mol Endocrinol. 2007 Jan;21(1):62-76 PMID: 17053040
  53. PGC-1alpha coactivates PDK4 gene expression via the orphan nuclear receptor ERRalpha: a mechanism for transcriptional control of muscle glucose metabolism.
    Mol Cell Biol. 2005 Dec;25(24):10684-94 PMID: 16314495
  54. Peroxisome proliferator-activated receptor coactivator-1alpha (PGC-1alpha) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-alpha and -gamma. Identification of novel leucine-rich interaction motif within PGC-1alpha.
    J Biol Chem. 2002 Oct 25;277(43):40265-74 PMID: 12181319
  55. Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERRalpha): crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha.
    J Biol Chem. 2004 Nov 19;279(47):49330-7 PMID: 15337744
  56. PGC-1alpha, a new therapeutic target in Huntington's disease?
    Cell. 2006 Nov 3;127(3):465-8 PMID: 17081970
  57. Estrogen-related receptor-gamma and peroxisome proliferator-activated receptor-gamma coactivator-1alpha regulate estrogen-related receptor-alpha gene expression via a conserved multi-hormone response element.
    J Mol Endocrinol. 2005 Apr;34(2):473-87 PMID: 15821111
  58. Estrogen receptor-related receptors: orphan receptors desperately seeking a ligand.
    J Mol Endocrinol. 2003 Dec;31(3):349-57 PMID: 14664699
  59. Receptor-interacting protein 140 differentially regulates estrogen receptor-related receptor transactivation depending on target genes.
    Mol Endocrinol. 2006 May;20(5):1035-47 PMID: 16439465
  60. RIP140 expression is stimulated by estrogen-related receptor alpha during adipogenesis.
    J Biol Chem. 2006 Oct 27;281(43):32140-7 PMID: 16923809
  61. Orphan nuclear receptors: shifting endocrinology into reverse.
    Science. 1999 Apr 30;284(5415):757-60 PMID: 10221899
  62. Modulation of estrogen receptor-alpha transcriptional activity by the coactivator PGC-1.
    J Biol Chem. 2000 May 26;275(21):16302-8 PMID: 10748020
  63. Regulation of the transcriptional coactivator PGC-1 via MAPK-sensitive interaction with a repressor.
    Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9713-8 PMID: 11481440
  64. The steroid receptor superfamily: more excitement predicted for the future.
    Mol Endocrinol. 1990 Mar;4(3):363-9 PMID: 2188115
  65. Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle.
    Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6570-5 PMID: 15100410
  66. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function.
    Genes Dev. 2004 Feb 15;18(4):357-68 PMID: 15004004
Article Info
Journal
Trends in endocrinology and metabolism: TEM
Abbr.
Trends Endocrinol Metab
ISSN
1043-2760
DOI
10.1016/j.tem.2008.07.005
Published
2008-10-00
Epub
2008-00-06
Pages
269-76
Language
English
Region
United States
NLM ID
9001516
PMCID
PMC2786240
Subset
IM
Grants
NIDDK NIH HHS · DK074660 · United States
NIDDK NIH HHS · R01 DK064951 · United States
NIDDK NIH HHS · R01 DK064951-05 · United States
NIDDK NIH HHS · R21 DK074660 · United States
NIDDK NIH HHS · R21 DK074660-02 · United States
NIDDK NIH HHS · DK064951 · United States
External Links
PubMed source DOI: 10.1016/j.tem.2008.07.005 PMC Full Text View journal details
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