A PPARγ-LXR-ABCA1 Pathway in Macrophages Is Involved in Cholesterol Efflux and Atherogenesis
Open accessAbstract
Previous work has implicated PPAR gamma in the regulation of CD36 expression and macrophage uptake of oxidized LDL (oxLDL). We provide evidence here that in addition to lipid uptake, PPAR gamma regulates a pathway of cholesterol efflux. PPAR gamma induces ABCA1 expression and cholesterol removal from macrophages through a transcriptional cascade mediated by the nuclear receptor LXR alpha. Ligand activation of PPAR gamma leads to primary induction of LXR alpha and to coupled induction of ABCA1. Transplantation of PPAR gamma null bone marrow into LDLR -/- mice results in a significant increase in atherosclerosis, consistent with the hypothesis that regulation of LXR alpha and ABCA1 expression is protective in vivo. Thus, we propose that PPAR gamma coordinates a complex physiologic response to oxLDL that involves particle uptake, processing, and cholesterol removal through ABCA1.
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Peripherally, LXRs and PPARγ participate in a coupled metabolic pathway in which activation of PPARγ induces expression of LXRα and its target genes abca1 and apoE.
“Peripherally, LXRs and PPARγ participate in a coupled metabolic pathway, whereby activation of PPARγ induces expression of LXRα and its target genes abca1 and apoE (Chawla et al., 2001; Seo et al., 2004; Yue and Mazzone, 2009).”
From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Chawla et al., 2001
The Introduction and Figures 1–3 (page numbers unavailable) support a PPARγ–LXRα pathway in macrophages: PPARγ activation induces LXRα, and PPARγ and LXR ligands cooperate to induce ABCA1. The passages identify ABCG1, not apoE, as the other induced gene; our copy does not support the attributed apoE induction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe PPARγ/LXRα pathway had been well documented in the periphery but was not recognized to be operative in the brain until this study.
“While this pathway has been well documented in the periphery, it was not recognized to be operative in the brain until now (Chawla et al., 2001).”
From Mechanisms Underlying the Rapid Peroxisome Proliferator-Activated Receptor-γ-Mediated Amyloid Clearance and Reversal of Cognitive Deficits in a Murine Model of Alzheimer's Disease (2012) · cites this paper as Chawla et al., 2001
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- is a high affinity ligand for peroxisome proliferator-activated recep- cholesterol efflux by the nuclear oxysterol receptor LXR␣. Proc. Natl. Acad. Sci. USA 97, 12097-12102.
- Ricote, M., Huang, J., Fajas, L., Li, A., Welch, J., Najib, J., Witztum, J.L., Auwerx, J., Palinski, W., and Glass, C.K. (1998a). Expression of the peroxisome proliferator-activated receptor ␥ (PPAR␥) in human atherosclerosis and regulation in macrophages by colony stimulat- ing factors and oxidized low density lipoprotein. Proc. Natl. Acad. Sci. USA 95, 7614-7619.
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- Authors
- Chawla, A., Boisvert, W. A., Lee, C.-H., Laffitte, B. A., Barak, Y., Joseph, S. B., Liao, D., Nagy, L., Edwards, P. A., Curtiss, L. K., Evans, R. M., & Tontonoz, P.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of California, Los Angeles (US)
- Howard Hughes Medical Institute (US)
- Scripps Research Institute (US)
- Corresponding author
- Evans, Ronald M.
- Tontonoz, Peter
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2001-01
- Volume
- 7
- Issue
- 1
- Pages
- 161-171
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W1986256219
- Cited by
- 1,347
- References
- 0
- Citations by year
- 2026: 28 · 2025: 37 · 2024: 42 · 2023: 25 · 2022: 36 · 2021: 57 · 2020: 45 · 2019: 37 · 2018: 46 · 2017: 50 · 2016: 49 · 2015: 49 · 2014: 52 · 2013: 57 · 2012: 62
- FWCI
- 84.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL007770, 2 T32 HL07770)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- PPARγ, liver X receptor alpha, ABCA1, cholesterol efflux, macrophages, atherosclerosis, oxidized LDL, CD36, LDL receptor, bone marrow transplantation, nuclear receptors, transcriptional regulation, lipid uptake
- MeSH terms
- Liver X Receptors, Animals, Arteriosclerosis, Cells, Cultured, DNA-Binding Proteins, Lipoproteins, LDL, Cholesterol, LDL, Macrophages, Mice, Inbred C57BL, Transcription Factors, Transcriptional Activation, Bone Marrow Transplantation, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, ATP-Binding Cassette Transporters, Mice, Orphan Nuclear Receptors, ATP Binding Cassette Transporter 1
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