Loss of embryonically-derived Kupffer cells during hypercholesterolemia accelerates atherosclerosis development
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Abstract
Hypercholesterolemia is a major risk factor for atherosclerosis and associated cardiovascular diseases. The liver plays a key role in the regulation of plasma cholesterol levels and hosts a large population of tissue-resident macrophages known as Kupffer cells (KCs). KCs are located in the hepatic sinusoids where they ensure key functions including blood immune surveillance. However, how KCs homeostasis is affected by the build-up of cholesterol-rich lipoproteins that occurs in the circulation during hypercholesterolemia remains unknown. Here, we show that embryo-derived KCs (EmKCs) accumulate large amounts of lipoprotein-derived cholesterol, in part through the scavenger receptor CD36, and massively expand early after the induction of hypercholesterolemia. After this rapid adaptive response, EmKCs exhibit mitochondrial oxidative stress and their numbers gradually diminish while monocyte-derived KCs (MoKCs) with reduced cholesterol-loading capacities seed the KC pool. Decreased proportion of EmKCs in the KC pool enhances liver cholesterol content and exacerbates hypercholesterolemia, leading to accelerated atherosclerotic plaque development. Together, our data reveal that KC homeostasis is perturbed during hypercholesterolemia, which in turn alters the control of plasma cholesterol levels and increases atherosclerosis.
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Infiltrating monocytes actively replace embryonic Kupffer cells during injury.
“In addition to competing for survival signals like CSF-1 (9, 33, 34), infiltrating monocytes actively replace embryonic KCs (EmKCs) during injury (35–37).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [36]
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- Authors
- Fima, R., Dussaud, S., Benbida, C., Blanchet, M., Lanthiez, F., Poupel, L., Brambilla, C., Gélineau, A., Dessena, M., Blanc, M., Lerévérend, C., Moreau, M., Boissonnas, A., Gautier, E. L., & Huby, T.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- University of Parma (IT)
- Corresponding author
- Huby, Thierry
- ORCID
- Venue
- Nature Communications
- Published
- 2024-09-27
- Volume
- 15
- Issue
- 1
- Pages
- 8341-8341
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11436809
- OpenAlex
- W4402922869
- Cited by
- 14
- References
- 63
- Citations by year
- 2026: 6 · 2025: 8
- FWCI
- 5.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
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- Nature Communications (publishedVersion, cc-by-nc-nd)
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- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-17-CE14-0044, ANR-21-CE14-0067-01)
- Fondation de France (00096295)
- Sorbonne Université Emergence programme
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- Kupffer cells, hypercholesterolemia, atherosclerosis, CD36, scavenger receptors, mitochondrial oxidative stress, atherosclerotic plaque
- MeSH terms
- Animals, Cholesterol, Female, Homeostasis, Hypercholesterolemia, Kupffer Cells, Liver, Male, Mice, Inbred C57BL, Monocytes, Mice, Knockout, Oxidative Stress, CD36 Antigens, Atherosclerosis, Mice, Plaque, Atherosclerotic
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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