LDL receptor deficiency or apoE mutations prevent remnant clearance and induce hypertriglyceridemia in mice
Open accessAbstract
We have used adenovirus-mediated gene transfer and bolus injection of purified apolipoprotein E (apoE) in mice to determine the contribution of LDL receptor family members in the clearance of apoE-containing lipoproteins in vivo and the factors that trigger hypertriglyceridemia. A low dose [5 x 10(8) plaque-forming units (pfu)] of an adenovirus expressing apoE4 did not normalize plasma cholesterol levels of apolipoprotein E-deficient (apoE(-/-)) x low density lipoprotein receptor-deficient (LDLr(-/-)) mice and induced hypertriglyceridemia. A similar phenotype of combined dyslipidemia was induced in apoE(-/-) or apoE(-/-) x LDLr(-/-) mice after infection with a low dose (4 x 10(8) pfu) of an adenovirus expressing the apoE4[R142V/R145V] mutant previously shown to be defective in receptor binding. In contrast, a low dose of 5 x 10(8) pfu of the apoE4-expressing adenovirus corrected hypercholesterolemia in apoE(-/-) mice and did not trigger hypertriglyceridemia. Bolus injection of purified apoE in apoE(-/-) x LDLr(-/-) mice did not clear plasma cholesterol levels and induced mild hypertriglyceridemia. In contrast, similar injection of apoE in apoE(-/-) mice cleared plasma cholesterol and caused transiently mild hypertriglyceridemia. These findings suggest that a) the LDL receptor alone can account for the clearance of apoE-containing lipoproteins in mice, and the contribution of other receptors is minimal, and b) defects in either the LDL receptor or in apoE that affect its interactions with the LDL receptor, increase the sensitivity to apoE-induced hypertriglyceridemia in mice.
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Defective recognition of apoE-containing lipoproteins due to mutations in apoE or LDL receptor deficiency may increase the sensitivity and severity of hypertriglyceridemia.
“We recently showed that defective recognition of apoEcontaining lipoproteins, either due to mutations in apoE or defi ciency in the LDL receptor, may increase the sensitivity and severity of hypertriglyceridemia ( 49 ).”
From Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4 (2011) · cites this paper as [49]
The concluding passage in the section on defective apoE–LDL receptor interactions states that either LDL receptor defects or apoE mutations increase the sensitivity and severity of hypertriglyceridemia. The finding is specifically for apoE-induced hypertriglyceridemia in mice; the citing sentence omits those limits. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe LDL receptor alone can account for the clearance of apoE-containing lipoprotein remnants in mice.
“The same study also showed that the LDL receptor alone can account for the clearance of apoE-containing lipoprotein remnants in mice”
From Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4 (2011) · cites this paper as [49]
The contribution of other members of the LDL-receptor family and heparan sulfate proteoglycans to the clearance of apoE-containing lipoprotein remnants in mice may be limited.
“and that the contribution of the other members of the LDL-receptor family and heparan sulfate proteoglycans (HSPG) may be limited ( 49 ).”
From Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4 (2011) · cites this paper as [49]
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Cites
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Borén, J., Chapman, M. J., Krauss, R. M., Packard, C. J., Bentzon, J. F., Binder, C. J., Daemen, M. J., Demer, L. L., Hegele, R. A., Nicholls, S. J., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz962 · Cited by 1,601 · see citing works
Hypertriglyceridemia in the genomic era: a new paradigm
Lewis, G. F., Xiao, C., & Hegele, R. A. (2015) · Endocrine Reviews · doi:10.1210/er.2014-1062 · Cited by 152 · see citing works
Georgiadou, D., Chroni, A., Vezeridis, A., Zannis, V. I., & Stratikos, E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027037 · Cited by 24 · see citing works
Self-citationVezeridis, A. M., Drosatos, K., & Zannis, V. I. (2011) · Journal of Lipid Research · doi:10.1194/jlr.m008409 · Cited by 11 · see citing works
Self-citationFotakis, P., Vezeridis, A., Dafnis, I., Chroni, A., Kardassis, D., & Zannis, V. I. (2014) · Journal of Lipid Research · doi:10.1194/jlr.m048348 · Cited by 4 · see citing works
Self-citation
- Authors
- Kypreos, K. E., & Zannis, V. I.
- Affiliations
- Boston University (US)
- Corresponding author
- Zannis, Vassilis I.
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 2006-03
- Volume
- 47
- Issue
- 3
- Pages
- 521-529
- ISSN
- 0022-2275 (ISSN-L)
- OpenAlex
- W2005702265
- Cited by
- 45
- References
- 4
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 2 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 1 · 2015: 1 · 2014: 4 · 2013: 1 · 2012: 6
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Lipid Research (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Heart Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL 68216, R01HL068216)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, LDL receptor, hypertriglyceridemia, hypercholesterolemia, APOE ε4, lipoprotein clearance, ApoE-deficient mice, LDL receptor-deficient mice, adenoviral gene transfer, dyslipidemia
- MeSH terms
- Animals, Apolipoproteins E, Cholesterol, Dose-Response Relationship, Drug, Female, Humans, Male, Models, Biological, Mutation, Protein Binding, Receptors, LDL, Recombinant Proteins, Time Factors, Tumor Cells, Cultured, Hypertriglyceridemia, Dyslipidemias, Mice
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