Cited by 688Adipose Tissue and MetabolismPeroxisome Proliferator-Activated ReceptorsMetabolism, Diabetes, and Cancer

ERRα and Gabpa/b specify PGC-1α-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle.

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Mootha, Vamsi K., Handschin, Christoph, Arlow, Dan, Xie, Xiaohui, St. Pierre, Julie, Sihag, Smita, Yang, Wenli, Altshuler, David +7 more·2004·Proceedings of the National Academy of Sciences

Abstract

Recent studies have shown that genes involved in oxidative phosphorylation (OXPHOS) exhibit reduced expression in skeletal muscle of diabetic and prediabetic humans. Moreover, these changes may be mediated by the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha). By combining PGC-1alpha-induced genome-wide transcriptional profiles with a computational strategy to detect cis-regulatory motifs, we identified estrogen-related receptor alpha (Erralpha) and GA repeat-binding protein alpha as key transcription factors regulating the OXPHOS pathway. Interestingly, the genes encoding these two transcription factors are themselves PGC-1alpha-inducible and contain variants of both motifs near their promoters. Cellular assays confirmed that Erralpha and GA-binding protein a partner with PGC-1alpha in muscle to form a double-positive-feedback loop that drives the expression of many OXPHOS genes. By using a synthetic inhibitor of Erralpha, we demonstrated its key role in PGC-1alpha-mediated effects on gene regulation and cellular respiration. These results illustrate the dissection of gene regulatory networks in a complex mammalian system, elucidate the mechanism of PGC-1alpha action in the OXPHOS pathway, and suggest that Erralpha agonists may ameliorate insulin-resistance in individuals with type 2 diabetes mellitus.

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Authors
Mootha, V. K., Handschin, C., Arlow, D., Xie, X., St. Pierre, J., Sihag, S., Yang, W., Altshuler, D., Puigserver, P., Patterson, N., Willy, P. J., Schulman, I. G., Heyman, R. A., Lander, E. S., & Spiegelman, B. M.
Affiliations
  • Broad Institute (US)
  • The Eli and Edythe L. Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, and Dana–Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115; and X-Ceptor Therapeutics Inc., San Diego, CA 92121
Venue
Proceedings of the National Academy of Sciences
Published
2004-04-20
Volume
101
Issue
17
Pages
6570-6575
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2131492087
Cited by
688
References
35
Citations by year
2026: 12 · 2025: 12 · 2024: 18 · 2023: 22 · 2022: 15 · 2021: 23 · 2020: 25 · 2019: 20 · 2018: 14 · 2017: 30 · 2016: 24 · 2015: 32 · 2014: 30 · 2013: 34 · 2012: 52
FWCI
27.59
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • edoc (University of Basel) (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
  • National Science Foundation
  • Howard Hughes Medical Institute
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
  • Schweizerische Akademie der Medizinischen Wissenschaften
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
PGC-1α, estrogen-related receptor alpha, GABPA, oxidative phosphorylation, skeletal muscle, type 2 diabetes, insulin resistance, transcriptional coactivator, cis-regulatory motifs, positive feedback loop, gene regulatory networks, cellular respiration
MeSH terms
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, ERRalpha Estrogen-Related Receptor, Animals, Base Sequence, Diabetes Mellitus, Experimental, DNA-Binding Proteins, Gene Expression Regulation, Oxidative Phosphorylation, Receptors, Estrogen, Transcription Factors, Transcription, Genetic, Transfection, Trans-Activators, Polymerase Chain Reaction, DNA Primers, Receptors, Cytoplasmic and Nuclear, Evolution, Molecular, GA-Binding Protein Transcription Factor, Mice

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