Cited by 1,195Peroxisome Proliferator-Activated ReceptorsAdipose Tissue and MetabolismCholesterol and Lipid Metabolism

The Coactivator PGC-1 Cooperates with Peroxisome Proliferator-Activated Receptor α in Transcriptional Control of Nuclear Genes Encoding Mitochondrial Fatty Acid Oxidation Enzymes

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Vega, Rick B., Huss, Janice M., Kelly, Daniel P.·2000·Molecular and Cellular Biology

Abstract

Peroxisome proliferator-activated receptor alpha (PPARalpha) plays a key role in the transcriptional control of genes encoding mitochondrial fatty acid beta-oxidation (FAO) enzymes. In this study we sought to determine whether the recently identified PPAR gamma coactivator 1 (PGC-1) is capable of coactivating PPARalpha in the transcriptional control of genes encoding FAO enzymes. Mammalian cell cotransfection experiments demonstrated that PGC-1 enhanced PPARalpha-mediated transcriptional activation of reporter plasmids containing PPARalpha target elements. PGC-1 also enhanced the transactivation activity of a PPARalpha-Gal4 DNA binding domain fusion protein. Retroviral vector-mediated expression studies performed in 3T3-L1 cells demonstrated that PPARalpha and PGC-1 cooperatively induced the expression of PPARalpha target genes and increased cellular palmitate oxidation rates. Glutathione S-transferase "pulldown" studies revealed that in contrast to the previously reported ligand-independent interaction with PPARgamma, PGC-1 binds PPARalpha in a ligand-influenced manner. Protein-protein interaction studies and mammalian cell hybrid experiments demonstrated that the PGC-1-PPARalpha interaction involves an LXXLL domain in PGC-1 and the PPARalpha AF2 region, consistent with the observed ligand influence. Last, the PGC-1 transactivation domain was mapped to within the NH(2)-terminal 120 amino acids of the PGC-1 molecule, a region distinct from the PPARalpha interacting domains. These results identify PGC-1 as a coactivator of PPARalpha in the transcriptional control of mitochondrial FAO capacity, define separable PPARalpha interaction and transactivation domains within the PGC-1 molecule, and demonstrate that certain features of the PPARalpha-PGC-1 interaction are distinct from that of PPARgamma-PGC-1.

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Crossref · 10.1128/mcb.20.5.1868-1876.2000

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  • PGC1α promotes fatty acid β-oxidation by functioning as a coactivator for PPARα and δ, which regulate expression of genes involved in mitochondrial fatty acid catabolism.

    “Besides its role in mitochondrial biogenesis, PGC 1α plays a pivotal role in promoting fatty acid β-oxidation by functioning as a coactivator for PPARα and δ, which in turn regulates the expression of genes involved in mitochondria fatty acid catabolism (Vega et al., 2000; Wang et al., 2003).”

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Authors
Vega, R. B., Huss, J. M., & Kelly, D. P.
Affiliations
  • Washington University in St. Louis (US)
  • Center for Cardiovascular Research, Departments of Medicine
Venue
Molecular and Cellular Biology
Published
2000-03-01
Volume
20
Issue
5
Pages
1868-1876
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
OpenAlex
W1996821192
Cited by
1,195
References
44
Citations by year
2026: 27 · 2025: 33 · 2024: 34 · 2023: 35 · 2022: 55 · 2021: 46 · 2020: 49 · 2019: 48 · 2018: 58 · 2017: 59 · 2016: 39 · 2015: 48 · 2014: 63 · 2013: 62 · 2012: 58
FWCI
10.72
Type
journal article
Language
en
Open access
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (5T32HL07275, T32HL007275)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK45416, R01DK045416)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
PGC-1, PPARα, transcriptional coactivator, transcriptional coactivation, mitochondrial beta-oxidation, LXXLL motif, 3T3-L1 adipocytes, palmitate oxidation, PPARγ
MeSH terms
Animals, Cell Line, Enzymes, Fatty Acids, Mitochondria, Nuclear Proteins, Oxidation-Reduction, Transcription Factors, Transcription, Genetic, Transfection, Receptors, Cytoplasmic and Nuclear, Mice

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