Cardiomyocyte-restricted peroxisome proliferator-activated receptor-δ deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy
Abstract
Fatty acid oxidation (FAO) is a primary energy source for meeting the heart's energy requirements. Peroxisome proliferator-activated receptor-delta (PPAR-delta) may have important roles in FAO. But it remains unclear whether PPAR-delta is required for maintaining basal myocardial FAO. We show that cre-loxP-mediated cardiomyocyte-restricted deletion of PPAR-delta in mice downregulates constitutive expression of key FAO genes and decreases basal myocardial FAO. These mice have cardiac dysfunction, progressive myocardial lipid accumulation, cardiac hypertrophy and congestive heart failure with reduced survival. Thus, chronic myocardial PPAR-delta deficiency leads to lipotoxic cardiomyopathy. Together, our data show that PPAR-delta is a crucial determinant of constitutive myocardial FAO and is necessary to maintain energy balance and normal cardiac function. We suggest that PPAR-delta is a potential therapeutic target in treating lipotoxic cardiomyopathy and other heart diseases.
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Impaired mitochondrial FAO in cardiomyocyte-restricted PPAR-δ knockout mice leads to heart failure and lipid accumulation in the absence of an increase in lipid uptake pathways.
“Impaired mitochondrial FAO in cardiomyocyte-restricted PPAR-δ knockout (KO) mice leads to heart failure and lipid accumulation in the absence of an increase in lipid uptake pathways, underscoring the important role of mitochondrial FAO capacity in contributing to the pathogenesis of lipotoxicity (47).”
From Cardiac remodeling in obesity (2008) · cites this paper as [47]
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- Authors
- Cheng, L., Ding, G., Qin, Q., Huang, Y., Lewis, W., He, N., Evans, R. M., Schneider, M. D., Brako, F. A., Xiao, Y., Chen, Y. E., & Yang, Q.
- Affiliations
- Morehouse School of Medicine (US)
- Emory University (US)
- Salk Institute for Biological Studies (US)
- Baylor College of Medicine (US)
- Corresponding author
- Yang, Qinglin
- Venue
- Nature Medicine
- Published
- 2004-10-10
- Volume
- 10
- Issue
- 11
- Pages
- 1245-1250
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2079796426
- Cited by
- 453
- References
- 26
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 14 · 2023: 8 · 2022: 15 · 2021: 23 · 2020: 18 · 2019: 10 · 2018: 16 · 2017: 17 · 2016: 17 · 2015: 18 · 2014: 24 · 2013: 24 · 2012: 25
- FWCI
- 12.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (5s06gm008248-23)
- National Heart, Lung, and Blood Institute (5 UH1 HL03676-02, UH1HL003676)
- National Institute of General Medical Sciences (S06 GM 08248)
- National Center for Research Resources (G12RR03034, G12RR003034)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- PPARδ, myocardial fatty acid oxidation, lipotoxic cardiomyopathy, myocardial energy metabolism, myocardial lipid accumulation, cardiac hypertrophy, congestive heart failure, cardiac dysfunction, therapeutic target
- MeSH terms
- Analysis of Variance, Animals, Fatty Acids, Gene Expression Regulation, Glucose, Malonyl Coenzyme A, Multienzyme Complexes, Cardiomyopathies, Myocardium, Oxidation-Reduction, Triglycerides, Immunoblotting, Protein Serine-Threonine Kinases, Gene Deletion, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, In Situ Nick-End Labeling, PPAR delta, Mice, AMP-Activated Protein Kinases
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