Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues
Open accessAbstract
The ATP-binding cassette transporter 1 (ABCA1) has recently been identified as a key regulator of high-density lipoprotein (HDL) metabolism, which is defective in familial HDL-deficiency syndromes such as Tangier disease. ABCA1 functions as a facilitator of cellular cholesterol and phospholipid efflux, and its expression is induced during cholesterol uptake in macrophages. To assess the role of macrophage ABCA1 in atherosclerosis, we generated low-density lipoprotein (LDL) receptor knockout (LDLr −/− ) mice that are selectively deficient in leukocyte ABCA1 (ABCA1 −/− ) by using bone marrow transfer (ABCA1 −/− → LDLr −/− ). Here we demonstrate that ABCA1 −/− → LDLr −/− chimeras develop significantly larger and more advanced atherosclerotic lesions compared with chimeric LDLr −/− mice with functional ABCA1 in hematopoietic cells. Targeted disruption of leukocyte ABCA1 function did not affect plasma HDL cholesterol levels. The amount of macrophages in liver and spleen and peripheral blood leukocyte counts is increased in the ABCA1 −/− → LDLr −/− chimeras. Our results provide evidence that leukocyte ABCA1 plays a critical role in the protection against atherosclerosis, and we identify ABCA1 as a leukocyte factor that controls the recruitment of inflammatory cells.
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Cholesterol efflux from cells to apolipoprotein A-I (apoA-I) acceptors via the ATP-binding cassette transporters ABCA1 and ABCG1 is central in the antiatherogenic mechanism.
“Cholesterol efflux from cells to apolipoprotein A-I (apoA-I) acceptors via the ATP-binding cassette transporters ABCA1 and ABCG1 is thought to be central in the antiatherogenic mechanism.”
From MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE <sup>−/−</sup> Mice (2012) · cites this paper as [13]
The Results and Discussion (p. 6) propose ABCA1-mediated cholesterol efflux as one possible explanation for ABCA1’s antiatherosclerotic effect. The Results and Discussion (p. 3) also describe apoA-I acquiring cholesterol from tissues through ABCA1. Our copy does not address ABCG1, so it does not support attributing the proposed mechanism to both transporters. (LLM, conf=0.88)
Experimental — accuracy not yet measuredStudies in mice with Abca1 deletion or overexpression generally support that ABCA1 prevents atherosclerosis by maintaining circulating HDL-C levels and cellular cholesterol efflux.
“Studies in mice in which the Abca1 locus is either deleted or overexpressed generally have supported the hypothesis that ABCA1 significantly prevents atherosclerosis by maintaining circulating HDL-C levels and cellular cholesterol efflux.10–13”
From MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE <sup>−/−</sup> Mice (2012) · cites this paper as [13]
The Results and Discussion (pp. 2, 5) show that leukocyte ABCA1 deficiency reduces macrophage cholesterol efflux and increases atherosclerotic lesions. But the paper reports no significant change in plasma HDL cholesterol in those mice (p. 3) and describes the protective effect as independent of plasma HDL (p. 6). Thus it supports ABCA1’s antiatherosclerotic role, but not the claim that this study’s effect operates by maintaining circulating HDL-C. (LLM, conf=0.88)
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Cites
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Horie, T., Baba, O., Kuwabara, Y., Chujo, Y., Watanabe, S., Kinoshita, M., Horiguchi, M., Nakamura, T., Chonabayashi, K., Hishizawa, M., et al. (2012) · Journal of the American Heart Association · doi:10.1161/jaha.112.003376 · Cited by 220 · see citing works
Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1
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- Authors
- Van Eck, M., Bos, I. S. T., Kaminski, W. E., Orsó, E., Rothe, G., Twisk, J., Böttcher, A., Van Amersfoort, E. S., Christiansen-Weber, T. A., Fung-Leung, W.-P., Van Berkel, T. J. C., & Schmitz, G.
- Affiliations
- Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, P.O. Box 9503, 2300 RA Leiden, The Netherlands; Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, D-93042 Regensburg, Germany; and R. W. Johnson Pharmaceutical Research Institute, San Diego, CA 92121
- Leiden University (NL)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2002-04-23
- Volume
- 99
- Issue
- 9
- Pages
- 6298-6303
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC122943
- OpenAlex
- W2103714932
- Cited by
- 348
- References
- 2
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 2 · 2022: 15 · 2021: 11 · 2020: 6 · 2019: 6 · 2018: 10 · 2017: 8 · 2016: 8 · 2015: 13 · 2014: 20 · 2013: 17 · 2012: 15
- FWCI
- 28.00
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- ABCA1, atherosclerosis, macrophage recruitment, HDL metabolism, LDL receptor knockout mice, bone marrow chimeras, cholesterol efflux, Tangier disease, inflammatory cell recruitment, atherosclerotic plaque
- MeSH terms
- Animals, Aorta, Apolipoproteins, Arteriosclerosis, Bone Marrow Cells, Cholesterol, Leukocytes, Lipids, Liver, Macrophages, Models, Genetic, Spleen, Time Factors, Triglycerides, Mice, Knockout, ATP-Binding Cassette Transporters, Genetic Predisposition to Disease, Mice, ATP Binding Cassette Transporter 1
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