ABCA1 Overexpression in the Liver of LDLr-KO Mice Leads to Accumulation of Pro-atherogenic Lipoproteins and Enhanced Atherosclerosis
Open accessAbstract
The identification of ABCA1 as a key transporter responsible for cellular lipid efflux has led to considerable interest in defining its role in cholesterol metabolism and atherosclerosis. In this study, the effect of overexpressing ABCA1 in the liver of LDLr-KO mice was investigated. Compared with LDLr-KO mice, ABCA1-Tg x LDLr-KO (ABCA1-Tg) mice had significantly increased plasma cholesterol levels, mostly because of a 2.8-fold increase in cholesterol associated with a large pool of apoB-lipoproteins. ApoB synthesis was unchanged but the catabolism of (125)I-apoB-VLDL and -LDL were significantly delayed, accounting for the 1.35-fold increase in plasma apoB levels in ABCA1-Tg mice. We also found rapid in vivo transfer of free cholesterol from HDL to apoB-lipoproteins in ABCA1-Tg mice, associated with a significant 2.7-fold increase in the LCAT-derived cholesteryl linoleate content found primarily in apoB-lipoproteins. ABCA1-Tg mice had 1.4-fold increased hepatic cholesterol concentrations, leading to a compensatory 71% decrease in de novo hepatic cholesterol synthesis, as well as enhanced biliary cholesterol, and bile acid secretion. CAV-1, CYP2b10, and ABCG1 were significantly induced in ABCA1-overexpressing livers; however, no differences were observed in the hepatic expression of CYP7alpha1, CYP27alpha1, or ABCG5/G8 between ABCA1-Tg and control mice. As expected from the pro-atherogenic plasma lipid profile, aortic atherosclerosis was increased 10-fold in ABCA1-Tg mice. In summary, hepatic overexpression of ABCA1 in LDLr-KO mice leads to: 1) expansion of the pro-atherogenic apoB-lipoprotein cholesterol pool size via enhanced transfer of HDL-cholesterol to apoB-lipoproteins and delayed catabolism of cholesterol-enriched apoB-lipoproteins; 2) increased cholesterol concentration in the liver, resulting in up-regulated hepatobiliary sterol secretion; and 3) significantly enhanced aortic atherosclerotic lesions.
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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 [11]
The Abstract describes ABCA1-mediated cholesterol transfer to apoA-I and calls nascent HDL formation a critical step in antiatherogenic reverse cholesterol transport. The Discussion instead associates ABCG1 with cholesterol removal by mature HDL, not apoA-I acceptors. The claim is therefore supported for ABCA1 but not for the stated acceptor of ABCG1-mediated efflux. (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 [11]
The Discussion says ABCA1 facilitates cellular cholesterol efflux and raises plasma HDL, and that macrophage ABCA1 expression is atheroprotective. But it describes conflicting results across mouse models: the Abstract reports no change in atherosclerosis with complete ABCA1 deficiency, while this study found increased atherosclerosis with hepatic overexpression. The claim's generalization about deletion and overexpression therefore exceeds what this paper supports. (LLM, conf=0.88)
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References 66 · Cited by 80
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- Authors
- Joyce, C. W., Wagner, E. M., Basso, F., Amar, M. J., Freeman, L. A., Shamburek, R. D., Knapper, C. L., Syed, J., Wu, J., Vaisman, B. L., Fruchart-Najib, J., Billings, E. M., Paigen, B., Remaley, A. T., Santamarina-Fojo, S., & Brewer, H. B.
- Affiliations
- National Institutes of Health (US)
- Jackson Laboratory (US)
- Corresponding author
- Wagner, Elke M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-11
- Volume
- 281
- Issue
- 44
- Pages
- 33053-33065
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2029498141
- Cited by
- 80
- References
- 66
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 6 · 2016: 1 · 2015: 3 · 2014: 6 · 2013: 5 · 2012: 4
- FWCI
- 6.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- ABCA1, LDL receptor knockout mice, atherosclerosis, cholesteryl linoleate, hepatic cholesterol synthesis, biliary cholesterol secretion, bile acid synthesis, Cyp2b10, ABCG1, caveolin-1, serum cholesterol, aortic atherosclerotic lesions
- MeSH terms
- Animals, Aorta, Biliary Tract, Cholesterol, Feces, Female, Gene Expression Regulation, Hemostasis, Humans, Intestinal Mucosa, Lipoproteins, Liver, Mice, Transgenic, Organ Specificity, Receptors, LDL, Sterols, Disease Progression, ATP-Binding Cassette Transporters, Oligonucleotide Array Sequence Analysis, Atherosclerosis, Lipid Metabolism, Mice, ATP Binding Cassette Transporter 1
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