Reciprocal regulation of inflammation and lipid metabolism by liver X receptors
Abstract
Macrophages have important roles in both lipid metabolism and inflammation and are central to the pathogenesis of atherosclerosis. The liver X receptors (LXRs) are established mediators of lipid-inducible gene expression, but their role in inflammation and immunity is unknown. We demonstrate here that LXRs and their ligands are negative regulators of macrophage inflammatory gene expression. Transcriptional profiling of lipopolysaccharide (LPS)-induced macrophages reveals reciprocal LXR-dependent regulation of genes involved in lipid metabolism and the innate immune response. In vitro, LXR ligands inhibit the expression of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase (COX)-2 and interleukin-6 (IL-6) in response to bacterial infection or LPS stimulation. In vivo, LXR agonists reduce inflammation in a model of contact dermatitis and inhibit inflammatory gene expression in the aortas of atherosclerotic mice. These findings identify LXRs as lipid-dependent regulators of inflammatory gene expression that may serve to link lipid metabolism and immune functions in macrophages.
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These trends are likely driven by ABCA1 expression extrinsic to T cells (i.e., in MCs), as cholesterol efflux has been shown to impair T cell expansion and activity.
“These trends are likely driven by ABCA1 expression extrinsic to T cells (ie: in MCs), as cholesterol efflux has been shown to impair T cell expansion and activity (39, 40).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [40]
Cholesterol efflux has been shown to impair T cell expansion and activity.
“as cholesterol efflux has been shown to impair T cell expansion and activity (39, 40).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [40]
Cholesterol is required to support the rapid clonal expansion of T cells post-activation.
“Cholesterol is required to support the rapid clonal expansion of T cells post-activation (39, 40); plasma membrane cholesterol abundance being required for T-cell receptor clustering and signaling (69).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [40]
Increased inflammation could be further augmented through decreased LXR activity.
“Increased inflammation could be further augmented through decreased LXR activity30.”
From Prolonged sleep restriction induces changes in pathways involved in cholesterol metabolism and inflammatory responses (2016) · cites this paper as [30]
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- Authors
- Joseph, S. B., Castrillo, A., Laffitte, B. A., Mangelsdorf, D. J., & Tontonoz, P.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Tontonoz, Peter
- Venue
- Nature Medicine
- Published
- 2003-01-13
- Volume
- 9
- Issue
- 2
- Pages
- 213-219
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W4230088158
- Cited by
- 1,158
- References
- 40
- Citations by year
- 2026: 33 · 2025: 36 · 2024: 36 · 2023: 46 · 2022: 40 · 2021: 58 · 2020: 45 · 2019: 52 · 2018: 45 · 2017: 56 · 2016: 46 · 2015: 46 · 2014: 65 · 2013: 50 · 2012: 63
- FWCI
- 51.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 660881)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Keywords
- liver X receptor, macrophages, inflammation, lipid metabolism, atherosclerosis, lipopolysaccharide, inducible nitric oxide synthase, cyclooxygenase-2, interleukin-6, innate immunity, contact dermatitis, LXR agonists, inflammatory gene expression
- MeSH terms
- Animals, Cells, Cultured, Inflammation, Lipids, Lipopolysaccharides, Signal Transduction, NF-kappa B, Receptors, Cytoplasmic and Nuclear, Nitric Oxide Synthase, Mice, Nitric Oxide Synthase Type II
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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