Peroxisome Proliferator-Activated Receptors and Atherogenesis: Regulators of Gene Expression in Vascular Cells
Abstract
A large body of data gathered over the past couple of years has identified the peroxisome proliferator-activated receptors (PPAR) α, γ, and β/δ as transcription factors exerting modulatory actions in vascular cells. PPARs, which belong to the nuclear receptor family of ligand-activated transcription factors, were originally described as gene regulators of various metabolic pathways. Although the PPARα, γ, and β/δ subtypes are ≈60% to 80% homologous in their ligand- and DNA-binding domains, significant differences in ligand and target gene specificities are observed. PPARα is activated by polyunsaturated fatty acids and oxidized derivatives and by lipid-modifying drugs of the fibrate family, including fenofibrate or gemfibrozil. PPARα controls expression of genes implicated in lipid metabolism. PPARγ, in contrast, is a key regulator of glucose homeostasis and adipogenesis. Ligands of PPARγ include naturally occurring FA derivatives, such as hydroxyoctadecadienoic acids (HODEs), prostaglandin derivatives such as 15-deoxyΔ 12,14 -prostaglandin J 2 , and glitazones, insulin-sensitizing drugs presently used to treat patients with type 2 diabetes. Ligands for PPARβ/δ are polyunsaturated fatty acids, prostaglandins, and synthetic compounds, some of which are presently in clinical development. PPARβ/δ stimulates fatty acid oxidation predominantly acting in muscle. All PPARs are expressed in vascular cells, where they exhibit antiinflammatory and antiatherogenic properties. In addition, studies in various animal models as well as clinical data suggest that PPARα and PPARγ activators can modulate atherogenesis in vivo. At present, no data are available relating to possible effects of PPARβ/δ agonists on atherogenesis. Given the widespread use of PPARα and PPARγ agonists in patients at high risk for cardiovascular disease, the understanding of their function in the vasculature is not only of basic interest but also has important clinical implications. This review will focus on the role of PPARs in the vasculature and summarize the present understanding of their effects on atherogenesis and its cardiovascular complications.
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n-3 PUFAs act as ligands for PPARα, triggering its activation and upregulation of genes involved in fatty acid oxidation.
“Specifically, n-3 PUFAs act as potent ligands for PPARα, triggering its activation and the subsequent upregulation of genes involved in fatty acid oxidation.32,33”
The TG-lowering effect of omega-3 in MASLD is attributed to their influence on master transcriptional regulators including PPARα, PPARγ, SREBP-1, and ChREBP.
“The triglyceride-lowering effect of omega-3 fatty acids in MASLD is attributed to their influence on master transcriptional regulators—including PPARα, PPARγ, SREBP-1, and ChREBP—that orchestrate fundamental hepatic lipid metabolic pathways.31,32”
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“This review found that although omega-3 supplementation was associated with reduced triglyceride levels in the overall MASLD population, the wide 95% prediction intervals spanning the zero effect line preclude definitive conclusions regarding its efficacy in future clinical settings.”
Influential
- Authors
- Marx, N., Duez, H., Fruchart, J.-C., & Staels, B.
- Affiliations
- Inserm (FR)
- From the Department of Internal Medicine II–Cardiology (N.M.), University of Ulm, Germany, and UR545 INSERM (H.D., J.-C.F., B.S.), Départment d’Athérosclérose, Institut Pasteur de Lille, Université de Lille, France.
- Venue
- Circulation Research
- Published
- 2004-05-14
- Volume
- 94
- Issue
- 9
- Pages
- 1168-1178
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2123404136
- Cited by
- 501
- References
- 10
- Citations by year
- 2026: 10 · 2025: 9 · 2024: 5 · 2023: 8 · 2022: 4 · 2021: 16 · 2020: 15 · 2019: 12 · 2018: 11 · 2017: 11 · 2016: 14 · 2015: 10 · 2014: 17 · 2013: 11 · 2012: 27
- FWCI
- 4.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- peroxisome proliferator-activated receptors, PPARα, PPARγ, PPARδ, atherogenesis, vascular cells, nuclear receptors, ligand specificity, polyunsaturated fatty acids, thiazolidinediones, hydroxyoctadecadienoic acids, anti-inflammatory activity, lipid metabolism, glucose homeostasis, adipogenesis, cardiovascular disease
- MeSH terms
- Animals, Arteriosclerosis, Clinical Trials as Topic, Drug Evaluation, Preclinical, Endothelium, Vascular, Gene Expression Regulation, Muscle, Smooth, Vascular, Transcription Factors, Transcription, Genetic, Drug Design, Consensus Sequence, Receptors, Cytoplasmic and Nuclear, Receptors, Retinoic Acid, Dimerization, Peroxisome Proliferators, Retinoid X Receptors, Rats
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