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The Coactivator PGC-1 Cooperates with Peroxisome Proliferator-Activated Receptor α in Transcriptional Control of Nuclear Genes Encoding Mitochondrial Fatty Acid Oxidation Enzymes
Open accessAbstract
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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“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).”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Vega et al., 2000
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Mechanisms underlying the resistance to diet-induced obesity in germ-free mice
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“…and β coactivate, one subset draws special attention; this includes NRF-1 and NRF-2 (Wu et al., 1999) and the nuclear hormone receptors, such as PPARα (Vega et al., 2000), PPARδ (Wang et al., 2003), ERRα (Huss et al., 2002; Huss et al., 2004; Kamei et al., 2003; Mootha et al., 2004; Schreiber et…”
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Metadata
- 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
- Publisher
- Informa UK Limited
- Published
- 2000-03-01
- Volume
- 20
- Issue
- 5
- Pages
- 1868-1876
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC85369
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › 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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