The Peroxisome Proliferator-activated Receptor δ Promotes Lipid Accumulation in Human Macrophages
Open accessAbstract
The peroxisome proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPARalpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARgamma (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPARalpha are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPARgamma agonists increase insulin sensitivity and are used in the management of type 2 diabetes. In contrast, there are no marketed drugs that selectively target PPARdelta (NR1C2) and the physiological roles of PPARdelta are unclear. In this report we demonstrate that the expression of PPARdelta is increased during the differentiation of human macrophages in vitro. In addition, a highly selective agonist of PPARdelta (compound F) promotes lipid accumulation in primary human macrophages and in macrophages derived from the human monocytic cell line, THP-1. Compound F increases the expression of genes involved in lipid uptake and storage such as the class A and B scavenger receptors (SRA, CD36) and adipophilin. PPARdelta activation also represses key genes involved in lipid metabolism and efflux, i.e. cholesterol 27-hydroxylase and apolipoprotein E. We have generated THP-1 sublines that overexpress PPARdelta and have confirmed that PPARdelta is a powerful promoter of macrophage lipid accumulation. These data suggest that PPARdelta may play a role in the pathology of diseases associated with lipid-filled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.
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The mediation of GW9662 effects by PPARδ is likely due to the abundant expression of PPARδ, a hallmark of THP-1 cell differentiation.
“This is likely reasoned by the abundant expression of PPARd, a hallmark of THP-1 cell differentiation (Vosper et al., 2001) (Supplemental Fig. 16).”
PPARd activation promotes lipid accumulation in THP-1 macrophages in the presence of serum.
“Consequently, the PPARd activation promotes lipid accumulation in THP-1 macrophages in the presence of serum (Vosper et al., 2001).”
The studies of Vosper et al. (2001) on PPARd and lipid accumulation in macrophages most accurately resemble our experimental setup because we did not use any lipoproteins as stimulus.
“As we did not use any lipoproteins as stimulus, the studies of Vosper et al. (2001) on PPARd and lipid accumulation in macrophages most accurately resemble our experimental setup.”
Treatment with a PPARd agonist upregulated expression of genes involved in lipid metabolism, including CD36 and PLIN2, in the study by Vosper et al.
“In line with our findings, the treatment with a PPARd agonist upregulated the expression of genes involved in lipid metabolism, including CD36 and PLIN2, in this study.”
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- Authors
- Vosper, H., Patel, L., Graham, T. L., Khoudoli, G. A., Hill, A., Macphee, C. H., Pinto, I., Smith, S. A., Suckling, K. E., Wolf, C. R., & Palmer, C. N. A.
- Affiliations
- Ninewells Hospital (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- Corresponding author
- Palmer, Colin N.A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-11
- Volume
- 276
- Issue
- 47
- Pages
- 44258-44265
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2103618523
- Cited by
- 268
- References
- 49
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 3 · 2018: 7 · 2017: 7 · 2016: 6 · 2015: 7 · 2014: 2 · 2013: 10 · 2012: 7
- FWCI
- 8.32
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion)
- Funders
- British Heart Foundation
- 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
- PPARδ, peroxisome proliferator-activated receptors, macrophage lipid accumulation, macrophage differentiation, compound F, scavenger receptors, CD36, adipophilin, apolipoprotein E, lipid metabolism, atherosclerosis, THP-1 cells
- MeSH terms
- Animals, Cell Line, Cholesterol, Gene Expression Regulation, Humans, Macrophages, Transcription Factors, Receptors, Cytoplasmic and Nuclear, Lipid Metabolism
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