Peroxisome Proliferator-Activated Receptor δ Is an Essential Transcriptional Regulator for Mitochondrial Protection and Biogenesis in Adult Heart
Open accessAbstract
Rationale: Peroxisome proliferator-activated receptors (PPARs) (α, γ, and δ/β) are nuclear hormone receptors and ligand-activated transcription factors that serve as key determinants of myocardial fatty acid metabolism. Long-term cardiomyocyte-restricted PPARδ deficiency in mice leads to depressed myocardial fatty acid oxidation, bioenergetics, and premature death with lipotoxic cardiomyopathy. Objective: To explore the essential role of PPARδ in the adult heart. Methods and Results: We investigated the consequences of inducible short-term PPARδ knockout in the adult mouse heart. In addition to a substantial transcriptional downregulation of lipid metabolic proteins, short-term PPARδ knockout in the adult mouse heart attenuated cardiac expression of both Cu/Zn superoxide dismutase and manganese superoxide dismutase, leading to increased oxidative damage to the heart. Moreover, expression of key mitochondrial biogenesis determinants such as PPARγ coactivator-1 were substantially decreased in the short-term PPARδ deficient heart, concomitant with a decreased mitochondrial DNA copy number. Rates of palmitate and glucose oxidation were markedly depressed in cardiomyocytes of PPARδ knockout hearts. Consequently, PPARδ deficiency in the adult heart led to depressed cardiac performance and cardiac hypertrophy. Conclusions: PPARδ is an essential regulator of cardiac mitochondrial protection and biogenesis and PPARδ activation can be a potential therapeutic target for cardiac disorders.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PPARβ can regulate catalase and SOD2.
“which can regulate catalase (22) and SOD2 (23).”
From TFAM Enhances Fat Oxidation and Attenuates High-Fat Diet–Induced Insulin Resistance in Skeletal Muscle (2019) · cites this paper as [23]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Aebi, H. (1984) · Methods in Enzymology · doi:10.1016/s0076-6879(84)05016-3 · Cited by 25,696 · see citing works
Wu, Z., Puigserver, P., Andersson, U., Zhang, C., Adelmant, G., Mootha, V., Troy, A., Cinti, S., Lowell, B., Scarpulla, R. C., et al. (1999) · Cell · doi:10.1016/s0092-8674(00)80611-x · Cited by 4,139 · see citing works
Metabolic control through the PGC-1 family of transcription coactivators
Lin, J., Handschin, C., & Spiegelman, B. M. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.05.004 · Cited by 2,130 · see citing works
Transcriptional paradigms in mammalian mitochondrial biogenesis and function
Scarpulla, R. C. (2008) · Physiological Reviews · doi:10.1152/physrev.00025.2007 · Cited by 1,666 · see citing works
PGC-1 coactivators: inducible regulators of energy metabolism in health and disease
Finck, B. N. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27794 · Cited by 1,427 · see citing works
Peroxisome-Proliferator-Activated Receptor δ Activates Fat Metabolism to Prevent Obesity
Wang, Y.-X., Lee, C.-H., Tiep, S., Yu, R. T., Ham, J., Kang, H., & Evans, R. M. (2003) · Cell · doi:10.1016/s0092-8674(03)00269-1 · Cited by 1,296 · see citing works
Regulation of Muscle Fiber Type and Running Endurance by PPARδ
Wang, Y.-X., Zhang, C.-L., Yu, R. T., Cho, H. K., Nelson, M. C., Bayuga-Ocampo, C. R., Ham, J., Kang, H., & Evans, R. M. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020294 · Cited by 1,089 · see citing works
The role of exercise and PGC1α in inflammation and chronic disease
Handschin, C., & Spiegelman, B. M. (2008) · Nature · doi:10.1038/nature07206 · Cited by 1,083 · see citing works
Lebovitz, R. M., Zhang, H., Vogel, H., Cartwright, J., Dionne, L., Lu, N., Huang, S., & Matzuk, M. M. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.18.9782 · Cited by 1,023 · see citing works
Transcriptional control of mitochondrial biogenesis: the central role of PGC-1
Ventura-Clapier, R., Garnier, A., & Veksler, V. (2008) · Cardiovascular Research · doi:10.1093/cvr/cvn098 · Cited by 932 · see citing works
Sohal, D. S., Nghiem, M. P., Crackower, M. A., Witt, S. A., Kimball, T. R., Tymitz, K. M., Penninger, J. M., & Molkentin, J. D. (2001) · Circulation Research · doi:10.1161/hh1301.092687 · Cited by 697 · see citing works
Mootha, V. K., Handschin, C., Arlow, D., Xie, X., St. Pierre, J., Sihag, S., Yang, W., Altshuler, D., Puigserver, P., Patterson, N., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401401101 · Cited by 688 · see citing works
Transcriptional Control of Mitochondrial Biogenesis and Function
Hock, M. B., & Kralli, A. (2009) · Annual Review of Physiology · doi:10.1146/annurev.physiol.010908.163119 · Cited by 616 · see citing works
Metabolic adaptations through the PGC‐1α and SIRT1 pathways
Rodgers, J. T., Lerín, C., Gerhart‐Hines, Z., & Puigserver, P. (2007) · FEBS Letters · doi:10.1016/j.febslet.2007.11.034 · Cited by 599 · see citing works
Barak, Y., Liao, D., He, W., Ong, E. S., Nelson, M. C., Olefsky, J. M., Boland, R., & Evans, R. M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.012610299 · Cited by 586 · see citing works
Gulick, T., Cresci, S., Caira, T., Moore, D. D., & Kelly, D. P. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.23.11012 · Cited by 560 · see citing works
High-fat diets cause insulin resistance despite an increase in muscle mitochondria
Hancock, C. R., Han, D.-H., Chen, M., Terada, S., Yasuda, T., Wright, D. C., & Holloszy, J. O. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802057105 · Cited by 538 · see citing works
Kunau, W. H. (1995) · Progress in Lipid Research · doi:10.1016/0163-7827(95)00011-9 · Cited by 506 · see citing works
Huss, J. M., Pineda‐Torra, I., Staels, B., Giguère, V., & Kelly, D. P. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.20.9079-9091.2004 · Cited by 485 · see citing works
Cheng, L., Ding, G., Qin, Q., Huang, Y., Lewis, W., He, N., Evans, R. M., Schneider, M. D., Brako, F. A., Xiao, Y., et al. (2004) · Nature Medicine · doi:10.1038/nm1116 · Cited by 453 · see citing works
Self-citationDjouadi, F., Weinheimer, C. J., Saffitz, J. E., Pitchford, C., Bastin, J., Gonzalez, F. J., & Kelly, D. P. (1998) · Journal of Clinical Investigation · doi:10.1172/jci3949 · Cited by 410 · see citing works
Gilde, A. J., van der Lee, K. A. J. M., Willemsen, P. H. M., Chinetti, G., van der Leij, F. R., Vusse, G. J., Staels, B., & van Bilsen, M. (2003) · Circulation Research · doi:10.1161/01.res.0000060700.55247.7c · Cited by 400 · see citing works
Dressel, U., Allen, T. L., Pippal, J. B., Rohde, P. R., Lau, P., & Muscat, G. E. O. (2003) · Molecular Endocrinology · doi:10.1210/me.2003-0151 · Cited by 370 · see citing works
Schuler, M. J., Ali, F., Chambon, C., Duteil, D., Bornert, J., Tardivel, A., Desvergne, B., Wahli, W., Chambon, P., & METZGER, D. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.10.003 · Cited by 368 · see citing works
Isolation and Culture of Adult Mouse Cardiac Myocytes
O’Connell, T. D., Rodrigo, M. C., & Simpson, P. C. (2006) · Humana Press eBooks · doi:10.1385/1-59745-214-9:271 · Cited by 341 · see citing works
Cardiomyocyte expression of PPARγ leads to cardiac dysfunction in mice
Son, N.-H., Park, T., Yamashita, H., Yokoyama, M., Huggins, L. A., Okajima, K., Homma, S., Szabolcs, M. J., Huang, L., & Goldberg, I. J. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30335 · Cited by 335 · see citing works
Mitochondrial deficiency and cardiac sudden death in mice lacking the MEF2A transcription factor
Naya, F. J., Black, B. L., Wu, H., Bassel‐Duby, R., Richardson, J. A., Hill, J. A., & Olson, E. N. (2002) · Nature Medicine · doi:10.1038/nm789 · Cited by 325 · see citing works
Nuclear receptors PPARβ/δ and PPARα direct distinct metabolic regulatory programs in the mouse heart
Burkart, E. M., Sambandam, N., Han, X., Gross, R. W., COURTOIS, M. R., Gierasch, C. M., Shoghi, K. I., Welch, M. J., & Kelly, D. P. (2007) · Journal of Clinical Investigation · doi:10.1172/jci32578 · Cited by 277 · see citing works
Girnun, G. D., Domann, F. E., Moore, S. A., & Robbins, M. E. C. (2002) · Molecular Endocrinology · doi:10.1210/me.2002-0020 · Cited by 258 · see citing works
Xu, Y., Kiningham, K. K., Devalaraja, M. N., Yeh, C., Majima, H. J., Kasarskis, E. J., & Clair, D. K. S. (1999) · DNA and Cell Biology · doi:10.1089/104454999314999 · Cited by 228 · see citing works
Li, J., Patel, V. V., Kostetskii, I., Xiong, Y., Chu, A. F., Jacobson, J. T., Yu, C., Morley, G. E., Molkentin, J. D., & Radice, G. L. (2005) · Circulation Research · doi:10.1161/01.res.0000181132.11393.18 · Cited by 223 · see citing works
Koitabashi, N., Bedja, D., Zaiman, A., Pinto, Y. M., Zhang, M., Gabrielson, K. L., Takimoto, E., & Kass, D. A. (2009) · Circulation Research · doi:10.1161/circresaha.109.198416 · Cited by 203 · see citing works
Sam, F., Kerstetter, D. L., Pimental, D. R., Mulukutla, S. R., Tabaee, A., Bristow, M. R., Colucci, W. S., & Sawyer, D. B. (2005) · Journal of Cardiac Failure · doi:10.1016/j.cardfail.2005.01.007 · Cited by 196 · see citing works
DING, G., FU, M., QIN, Q., Lewis, W., Kim, H. W., Fukai, T., Bacanamwo, M., CHEN, Y., Schneider, M. D., & Mangelsdorf, D. J. (2007) · Cardiovascular Research · doi:10.1016/j.cardiores.2007.06.027 · Cited by 158 · see citing works
Yoo, H. Y., Chang, M. S., & Rho, H. M. (1999) · Gene · doi:10.1016/s0378-1119(99)00176-6 · Cited by 121 · see citing works
Cheng, L., Ding, G., Qin, Q., Xiao, Y., Woods, D., Chen, Y. E., & Yang, Q. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.11.127 · Cited by 121 · see citing works
Self-citationPPARδ, but not PPARα, activates PGC-1α gene transcription in muscle
Hondares, E., Pineda-Torra, I., Iglesias, R., Staels, B., Villarroya, F., & Giralt, M. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.01.092 · Cited by 120 · see citing works
Roles of PPARs on regulating myocardial energy and lipid homeostasis
Yang, Q., & Li, Y. (2007) · Journal of Molecular Medicine · doi:10.1007/s00109-007-0170-9 · Cited by 107 · see citing works
Self-citationFrancke, U., & Taggart, R. T. (1979) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.76.10.5230 · Cited by 99 · see citing works
Nagao, M., Parimoo, B., & Tanaka, K. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(20)80500-6 · Cited by 87 · see citing works
Hajduch, É., Darakhshan, F., & Hundal, H. S. (1998) · Diabetologia · doi:10.1007/s001250050993 · Cited by 79 · see citing works
Muscle insulin resistance: a case of fat overconsumption, not mitochondrial dysfunction
Kraegen, E. W., Cooney, G. J., & Turner, N. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803901105 · Cited by 62 · see citing works
Peroxisome proliferator-activated receptor δ regulates mitofusin 2 expression in the heart
Li, Y., Yin, R., Liu, J., Wang, P., Wu, S., Luo, J., Zhelyabovska, O., & Yang, Q. (2009) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2009.02.020 · Cited by 36 · see citing works
Self-citationLi, Y., Cheng, L., Qin, Q., Liu, J., Lo, W.-K., Brako, L. A., & Yang, Q. (2009) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2009.07.001 · Cited by 23 · see citing works
Self-citationOpen‐chest 31P magnetic resonance spectroscopy of mouse heart at 4.7 Tesla
Lee, J. J., Hu, Q., Nakamura, Y., et al. (2006) · Journal of Magnetic Resonance Imaging · doi:10.1002/jmri.20766 · Cited by 15 · see citing works
Molecular regulation of lipotoxicity in the heart
Yang, Q., & Cheng, L. (2005) · Drug Discovery Today Disease Mechanisms · doi:10.1016/j.ddmec.2005.05.032 · Cited by 8 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Koh, J.-H., Johnson, M. L., Dasari, S., LeBrasseur, N. K., Vuckovic, I., Henderson, G. C., Cooper, S. A., Manjunatha, S., Ruegsegger, G. N., Shulman, G. I., et al. (2019) · Diabetes · doi:10.2337/db19-0088 · Cited by 92 · see citing works
Biology and Therapeutic Applications of Peroxisome Proliferator- Activated Receptors
P. Menendez-Gutierrez, M., Roszer, T., & Ricote, M. (2012) · Current Topics in Medicinal Chemistry · doi:10.2174/156802612799436669 · Cited by 62 · see citing works
- Authors
- Wang, P., Liu, J., Li, Y., Wu, S., Luo, J., Yang, H., Subbiah, R., Chatham, J., Zhelyabovska, O., & Yang, Q.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Yang, Qinglin
- Venue
- Circulation Research
- Published
- 2010-03-19
- Volume
- 106
- Issue
- 5
- Pages
- 911-919
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC2993321
- OpenAlex
- W2072261695
- Cited by
- 110
- References
- 46
- Citations by year
- 2025: 4 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 9 · 2019: 5 · 2018: 12 · 2017: 11 · 2016: 6 · 2015: 6 · 2014: 8 · 2013: 5 · 2012: 12
- FWCI
- 3.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01hl084456-06)
- National Heart, Lung, and Blood Institute (R01-HL084456, 1R01 HL084456, R01HL085499)
- National Center for Complementary and Integrative Health (R21AT003734)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- PPARδ, mitochondrial protection, oxidative stress, superoxide dismutase, PGC-1, mitochondrial DNA copy number, fatty acid oxidation, cardiac hypertrophy, nuclear receptors, transcriptional regulation
- MeSH terms
- Superoxide Dismutase-1, Superoxide Dismutase 2, Aging, Animals, Antioxidants, Cells, Cultured, DNA, Mitochondrial, Energy Metabolism, Glucose, Cardiomegaly, Homeostasis, Mice, Inbred C57BL, Mitochondria, Heart, Oxidation-Reduction, RNA, Messenger, Superoxide Dismutase, Transcription, Genetic, Gene Expression Regulation, Enzymologic, Mice, Knockout, Oxidative Stress, Ventricular Dysfunction, Left, Palmitic Acid, Myocytes, Cardiac, PPAR delta, Lipid Metabolism, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review