Hepatic ATP-Binding Cassette Transporter A1 Is a Key Molecule in High-Density Lipoprotein Cholesteryl Ester Metabolism in Mice
Open accessAbstract
Objective— Mutations in ATP-binding cassette transporter A1 (ABCA1), the cellular lipid transport molecule mutated in Tangier disease, result in the rapid turnover of high-density lipoprotein (HDL)–associated apolipoproteins that presumably are cleared by the kidneys. However, the role of ABCA1 in the liver for HDL apolipoprotein and cholesteryl ester (CE) catabolism in vivo is unknown. Methods and Results— Murine HDL was radiolabeled with 125 I in its apolipoprotein and with [ 3 H]cholesteryl oleyl ether in its CE moiety. HDL protein and lipid metabolism in plasma and HDL uptake by tissues were investigated in ABCA1-overexpressing bacterial artificial chromosome (BAC)–transgenic (BAC + ) mice and in mice harboring deletions of total (ABCA1 −/− ) and liver-specific ABCA1 (ABCA1 −L/−L ). In BAC + mice with elevated ABCA1 expression, fractional catabolic rates (FCRs) of both the protein and the lipid tracer were significantly decreased in plasma and in the liver, yielding a diminished hepatic selective CE uptake from HDL. In contrast, ABCA1 −/− or ABCA1 −L/−L mice had significantly increased plasma and liver FCRs for both HDL tracers. An ABCA1 deficiency was associated with increased selective HDL CE uptake by the liver under all experimental conditions. Conclusions— Hepatic ABCA1 has a critical role for HDL catabolism in plasma and for HDL selective CE uptake by the liver.
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ABCA1-mediated cholesterol export is essential for the formation of HDL particles, because liver- and intestine-specific ABCA1 knockout mice show strong reductions in HDL levels.
“This process seems to be essential for the formation of HDL particles because liver-and intestine-specific knockout mice for ABCA1 show strong reductions in HDL levels (45)(46)(47).”
From Expression of miR-33 from an SREBP2 Intron Inhibits Cholesterol Export and Fatty Acid Oxidation* (2010) · cites this paper as [46]
The Abstract reports an 80% reduction in plasma HDL cholesterol in liver-specific ABCA1 knockout mice, supporting the liver-specific part of the claim. The paper does not report an intestine-specific knockout or its HDL levels. Its Discussion also says low HDL reflects increased catabolism as well as decreased synthesis, so the reduction alone does not establish a defect solely in particle formation. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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ABCA1, Tangier Disease, and Lipid Flopping
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- Authors
- Singaraja, R. R., Stahmer, B., Brundert, M., Merkel, M., Heeren, J., Bissada, N., Kang, M., Timmins, J. M., Ramakrishnan, R., Parks, J. S., Hayden, M. R., & Rinninger, F.
- Affiliations
- University of British Columbia (CA)
- From the University of British Columbia (R.R.S., N.B., M.K., M.R.H.), Vancouver, Canada; University Hospital Eppendorf (B.S., M.B., M.M., J.H., F.R.), Hamburg, Germany; Wake Forest University (J.M.T., J.S.P.), Winston-Salem, NC; and Columbia University (R.R.), New York, NY.
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2006-08
- Volume
- 26
- Issue
- 8
- Pages
- 1821-1827
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2149731417
- Cited by
- 33
- References
- 28
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2021: 1 · 2019: 2 · 2014: 5 · 2012: 3
- FWCI
- 3.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 49373, HL 07115, P01HL049373)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- ABCA1, ABC transporters, high-density lipoprotein, HDL catabolism, fractional catabolic rate, Tangier disease
- MeSH terms
- Animals, Cholesterol, Cholesterol Esters, Lipoproteins, HDL, Liver, Mice, Transgenic, Tissue Distribution, Mice, Knockout, ATP-Binding Cassette Transporters, Chromosomes, Artificial, Bacterial, Scavenger Receptors, Class B, Mice, ATP Binding Cassette Transporter 1
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