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Cited by 447Cholesterol and Lipid MetabolismLipid metabolism and disordersLipoproteins and Cardiovascular Health

Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I

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Timmins, Jenelle M., Lee, Ji-Young, Boudyguina, Elena, Kluckman, Kimberly D., Brunham, Liam R., Mulya, Anny, Gebre, Abraham K., Coutinho, Jonathan M. +5 more·2005·Journal of Clinical Investigation
DOI 10.1172/jci23915PMC PMC1074680
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Abstract

Patients with Tangier disease exhibit extremely low plasma HDL concentrations resulting from mutations in the ATP-binding cassette, sub-family A, member 1 (ABCA1) protein. ABCA1 controls the rate-limiting step in HDL particle assembly by mediating efflux of cholesterol and phospholipid from cells to lipid-free apoA-I, which forms nascent HDL particles. ABCA1 is widely expressed; however, the specific tissues involved in HDL biogenesis are unknown. To determine the role of the liver in HDL biogenesis, we generated mice with targeted deletion of the second nucleotide-binding domain of Abca1 in liver only (Abca1(-L/-L)). Abca1(-L/-L) mice had total plasma and HDL cholesterol concentrations that were 19% and 17% those of wild-type littermates, respectively. In vivo catabolism of HDL apoA-I from wild-type mice or human lipid-free apoA-I was 2-fold higher in Abca1(-L/-L) mice compared with controls due to a 2-fold increase in the catabolism of apoA-I by the kidney, with no change in liver catabolism. We conclude that in chow-fed mice, the liver is the single most important source of plasma HDL. Furthermore, hepatic, but not extrahepatic, Abca1 is critical in maintaining the circulation of mature HDL particles by direct lipidation of hepatic lipid-poor apoA-I, slowing its catabolism by the kidney and prolonging its plasma residence time.

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  • The liver and intestine are the major sources of HDL-C.

    “which is consistent with the results that the liver and intestine are the major sources of HDL-C.39,40”

    From MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE <sup>−/−</sup> Mice (2012) · cites this paper as [39]

    The Introduction (p. 1) says the liver and intestine are the two quantitatively important sites of apoA-I synthesis and secretion, but it does not establish that both are major sources of HDL-C. The study concludes that the liver is the single most important source of plasma HDL in chow-fed mice; it does not determine the intestine’s contribution to HDL-C. (LLM, conf=0.86)

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Research works printed but not linked: 4

  1. [18]McNeish, J., et al. 2000. High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc. Natl. Acad. Sci. U. S. A. 97 :4245-4250.
  2. [36]Wang, N., Lan, D., Chen, W., Matsuura, F., and Tall, A.R. 2004. ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to highdensity lipoproteins. Proc. Natl. Acad. Sci. U. S. A. 101 :9774-9779.
  3. [37]Van Eck, M., et al. 2002. Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues. Proc. Natl. Acad. Sci. U. S. A. 99 :6298-6303.
  4. [45]Parks, J.S., Gebre, A.K., and Furbee, J.W., Jr. 1998. Lecithin-cholesterol acyltransferase. Assay of cholesterol esterification and phospholipase A2 activities. In Methods in molecular biolog y. M. Doolittle and K. Reue, editors. Humana Press. Totowa, New Jersey, USA. 123-131.

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Authors
Timmins, J. M., Lee, J.-Y., Boudyguina, E., Kluckman, K. D., Brunham, L. R., Mulya, A., Gebre, A. K., Coutinho, J. M., Colvin, P. L., Smith, T. L., Hayden, M. R., Maeda, N., & Parks, J. S.
Affiliations
  • Wake Forest University Health Sciences (US)
  • Wake Forest University (US)
  • University of British Columbia (CA)
  • University of Maryland, Baltimore (US)
Corresponding author
Parks, John S.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2005-04-07
Volume
115
Issue
5
Pages
1333-1342
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci23915
PMC
PMC1074680
OpenAlex
W2128006949
Cited by
447
References
2
Citations by year
2026: 2 · 2024: 4 · 2023: 8 · 2022: 8 · 2021: 9 · 2020: 16 · 2019: 11 · 2018: 12 · 2017: 17 · 2016: 19 · 2015: 15 · 2014: 38 · 2013: 34 · 2012: 27
FWCI
36.28
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
Funders
  • Heart and Stroke Foundation of Canada
  • Wake Forest University
  • Michael Smith Health Research BC
  • Killam Trusts
  • National Institutes of Health
  • Canadian Institutes of Health Research
  • National Heart, Lung, and Blood Institute (HL 42630, HL 49373, R37HL042630, HL 07115, T32HL007115, R01HL042630, P01HL049373)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
ABCA1, Tangier disease, HDL biogenesis, hypoalphalipoproteinemia, kidney, liver, HDL cholesterol, lipid modification
MeSH terms
Animals, Genotype, Humans, Kidney, Lipoproteins, HDL, Tangier Disease, Apolipoprotein A-I, Macrophages, Peritoneal, Mice, Knockout, Gene Targeting, ATP-Binding Cassette Transporters, Hepatocytes, Mice, ATP Binding Cassette Transporter 1

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