Cholesterol and apolipoprotein B metabolism in Tangier disease
Abstract
Tangier disease (TD), caused by mutations in the gene encoding ATP-binding cassette 1 (ABCA1), is a rare genetic disorder in which homozygotes have a marked deficiency of high density lipoproteins (HDL), as well as concentrations of low density lipoproteins (LDL) that are typically 40% of normal. Although it is well known that the reduced levels of HDL in TD are due to hypercatabolism, the mechanism responsible for the low LDL levels has not been defined. Recently, it has been reported that intestinal cholesterol absorption is altered in ABCA1 deficient mice, suggesting that aberrant cholesterol metabolism may contribute to the LDL reductions in TD. In order to explore this possibility, as well as to define the role that ABCA1 plays in the metabolism of apolipoprotein (apoB)-containing lipoproteins, we determined the kinetics of apoB-100 within lipoproteins, and cholesterol absorption, biosynthesis, and turnover, in a compound heterozygote for TD. The levels of HDL cholesterol, LDL cholesterol and LDL apoB-100 in this subject were 7, 27 and 69% of normal, respectively, the latter of which was due to a two-fold increase in LDL catabolism (0.54 vs. 0.26+/-0.07 poolsday(-1)) relative to controls (n=11). NMR analysis of plasma lipoproteins revealed that 91% of the LDL cholesterol in the TD subject was contained within small, dense LDL, as compared with only 20% for controls (n=70). Cholesterol absorption was 97% of the value for controls (n=15) in the TD subject, at 45%, with cho…
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Plasma kinetic studies in humans with loss-of-function mutations in ABCA1 demonstrated increased catabolism of HDL and LDL B-100, suggesting decreased stability of poorly lipidated lipoprotein particles.
“These studies demonstrated that the catabolism of both high-density lipoprotein (HDL) and low-density lipoprotein apolipoprotein B-100 (LDL B-100) were increased in the plasma of these individuals [44,45], suggesting decreased stability of poorly lipidated lipoprotein particles.”
From Measurement of apolipoprotein E and amyloid β clearance rates in the mouse brain using bolus stable isotope labeling (2012) · cites this paper as [45]
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Brunham, L. R. (2006) · Journal of Clinical Investigation · doi:10.1172/jci27352 · Cited by 519 · see citing works
“However, this is unlikely to be the sole mechanism, since patients with apoA-I deficiency also lack plasma HDL cholesterol but do not exhibit the reduction in LDL cholesterol observed in Tangier disease (64), and mice that lack ABCA1 globally or in the liver have reduced LDL cholesterol but do not have CETP (16, 41).”
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“One issue in addressing this question is that humans with Tangier disease have significantly reduced total plasma cholesterol, and in particular, LDL cholesterol is reduced by 40%–70% (69).”
BackgroundThe Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease
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“A review of 185 TD cases reported that 51% of patients aged 40 to 65 years had premature CHD and suggested that reduced low-density lipoproteincholesterol (LDL-C) levels in TD patients provide cardiovascular protection, while TD patients with normal LDL-C levels are likely to develop premature CHD [10].”
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“A patient with Tangier disease had a cholesterol absorption percentage similar to those of control subjects ( 25 ).”
Tissue-Specific Roles of ABCA1 Influence Susceptibility to Atherosclerosis
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“Tangier disease homozygotes have total plasma cholesterol and LDL cholesterol levels approximately 40% lower than controls [15], which may protect their islets from cholesterol accumulation and potentially explain why these patients are not generally reported to be at high risk for diabetes.”
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“able to a 2-fold increase in the fractional catabolic rate of LDL.(45) Chow-fed HSKO mice demonstrated a 50% lower plasma LDL concentration, a 2-fold increase in (125)I-LDL”
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“Likewise, measurement of fractional cholesterol absorption in a single patient with Tangier disease revealed a value in the ‘normal range’ (Schaeffer et al. 2001).”
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“Our conclusions are based on correlational analyses, which do not prove cause-effect relationships, and it is possible that decreased cellular cholesterol efflux may result in accelerated catabolism of VLDL-apoB-100, as shown in Tangier disease (25).”
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Association of a Novel Homozygous Variant in ABCA1 Gene with Tangier Disease
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BackgroundInfluentialSelf-citation
- Authors
- Schaefer, E. J., Brousseau, M. E., Diffenderfer, M. R., Cohn, J. S., Welty, F. K., O'Connor, J., Dolnikowski, G. G., Wang, J., Hegele, R. A., & Jones, P. J.
- Affiliations
- Tufts University (US)
- Montreal Clinical Research Institute (CA)
- Western University (CA)
- Corresponding author
- Schaefer, Ernst J
- ORCID
- Venue
- Atherosclerosis
- Publisher
- Elsevier BV
- Published
- 2001-11
- Volume
- 159
- Issue
- 1
- Pages
- 231-236
- ISSN
- 0021-9150 (ISSN-L)
- OpenAlex
- W2085997836
- Cited by
- 52
- References
- 26
- Citations by year
- 2025: 3 · 2023: 1 · 2022: 1 · 2021: 1 · 2018: 2 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 4 · 2012: 3
- FWCI
- 3.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Atherosclerosis (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Agriculture
- National Institutes of Health
- Agricultural Research Service
- National Heart, Lung, and Blood Institute (HL 60935, R01HL060935)
- National Center for Research Resources (M01RR000054)
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- Tangier disease, ABCA1, apolipoprotein B-100, LDL catabolism, HDL deficiency, cholesterol absorption, cholesterol biosynthesis, cholesterol turnover, small dense LDL, lipoprotein metabolism, compound heterozygosity
- MeSH terms
- Aged, Apolipoproteins B, Cholesterol, Heterozygote, Homozygote, Humans, Cholesterol, LDL, Male, Middle Aged, Magnetic Resonance Spectroscopy, Tangier Disease, ATP-Binding Cassette Transporters, Apolipoprotein B-100, ATP Binding Cassette Transporter 1
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