Peroxisome proliferator-activated receptor δ promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage
Abstract
Significant attention has focused on the role of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, recent advances have identified triglyceride-rich lipoproteins [e.g., very LDL (VLDL)] as independent risk predictors for this disease. We have previously demonstrated peroxisome proliferator-activated receptor (PPAR)delta, but not PPARgamma, is the major nuclear VLDL sensor in the macrophage, which is a crucial component of the atherosclerotic lesion. Here, we show that, in addition to beta-oxidation and energy dissipation, activation of PPARdelta by VLDL particles induces key genes involved in carnitine biosynthesis and lipid mobilization mediated by a recently identified TG lipase, transport secretion protein 2 (also named desnutrin, iPLA2zeta, and adipose triglyceride lipase), resulting in increased fatty acid catabolism. Unexpectedly, deletion of PPARdelta results in derepression of target gene expression, a phenotype similar to that of ligand activation, suggesting that unliganded PPARdelta suppresses fatty acid utilization through active repression, which is reversed upon ligand binding. This unique transcriptional mechanism assures a tight control of the homeostasis of VLDL-derived fatty acid and provides a therapeutic target for other lipid-related disorders, including dyslipidemia and diabetes, in addition to coronary artery disease.
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PPARd selectively responds to different stimuli of lipid metabolism; VLDL reliably activates PPARd, whereas HDL and LDL do not.
“Furthermore, PPARd selectively responds to different”
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Peroxisome-Proliferator-Activated Receptor δ Activates Fat Metabolism to Prevent Obesity
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Self-citationNew Perspectives on Atherogenesis: Role of Abnormal Triglyceride-Rich Lipoprotein Metabolism
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- Authors
- Lee, C.-H., Kang, K., Mehl, I. R., Nofsinger, R., Alaynick, W. A., Chong, L.-W., Rosenfeld, J. M., & Evans, R. M.
- Affiliations
- Harvard University (US)
- Salk Institute for Biological Studies (US)
- Chemicom International, 28820 Single Oak Drive, Temecula, CA 92590
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-02-07
- Volume
- 103
- Issue
- 7
- Pages
- 2434-2439
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2000251574
- Cited by
- 98
- References
- 5
- Citations by year
- 2025: 4 · 2024: 1 · 2022: 5 · 2020: 8 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 6 · 2015: 4 · 2014: 6 · 2013: 7 · 2012: 8
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- March of Dimes Foundation
- National Institutes of Health
- National Heart, Lung, and Blood Institute (P50 HL56898)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK057978, R01DK057978, DK57978)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- PPARδ, VLDL, macrophages, fatty acid degradation, atherosclerosis, carnitine biosynthesis, adipose triglyceride lipase, lipid mobilization, transcriptional repression, triglyceride-rich lipoproteins, dyslipidemia, diabetes mellitus
- MeSH terms
- Acyltransferases, Animals, Carboxylic Ester Hydrolases, Carnitine, Fatty Acids, Gene Expression Regulation, Lipase, Lipoproteins, VLDL, Macrophages, Oxidation-Reduction, Gene Deletion, PPAR delta, Lipid Metabolism, Mice
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