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Targeted Replacement of the Mouse Apolipoprotein E Gene with the Common Human APOE3 Allele Enhances Diet-induced Hypercholesterolemia and Atherosclerosis
Open accessAbstract
Apolipoprotein (apo) E, a constituent of several lipoproteins, is a ligand for the low density lipoprotein receptor, and this interaction is important for maintaining cholesterol and triglyceride homeostasis. We have used a gene replacement strategy to generate mice that express the human apoE3 isoform in place of the mouse protein. The levels of apoE mRNA in various tissues are virtually the same in the human apoE3 homozygous (3/3) mice and their littermates having the wild type mouse allele (+/+). Total cholesterol and triglyceride levels in fasted plasma from the 3/3 mice were not different from those in the +/+ mice, when maintained on a normal (low fat) chow diet. We found, however, notable differences in the distribution of plasma lipoproteins and apolipoprotein E between the two groups: beta-migrating lipoproteins and plasma apoB100 levels are decreased in the 3/3 mice, and the apoE distribution is shifted from high density lipoproteins to larger lipoprotein particles. In addition, the fractional catabolic rate of exogenously administered remnant particles without apoE was 6-fold slower in the 3/3 mice compared with the +/+ mice. When the 3/3 and +/+ animals were fed a high fat/high cholesterol diet, the 3/3 animals responded with a dramatic increase (5-fold) in total cholesterol compared with the +/+ mice (1.5-fold), and after 12 weeks on this same diet the 3/3 animals developed significantly (at least 13-fold) larger atherosclerotic plaques in the aortic sinus area t…
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In the citing paper
“To determine the gene dosage effect of human APOE3 and APOE4 on amyloid deposition, we used knock-in mouse models in which the endogenous murine Apoe gene is replaced with the APOE3 or APOE4 gene.”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as Sullivan et al., 1997
In the citing paper
“APOE ε2-TR or APOE ε4-TR mice retain regulatory sequences of the mouse Apoe gene and the noncoding murine exon 1 surrounding the inserted human exons 2′, 3′, and 4′ [17,18] and therefore, they express the human apoE protein at physiological levels.”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [18]
In the citing paper
“APOE targeted replacement mice, which express human APOE in place of their mouse Apoe gene and which do not develop overt AD pathology28,29”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [29]
In the citing paper
“These APOE TR mice were previously generated by removing and replacing the endogenous mouse Apoe gene with the human APOE gene 51,52 .”
From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [51]
In the citing paper
“APOE-TR mice, which are genetically chimeric, i.e. contain the mouse 5’ regulatory region but human exons 2–4 (Knouff et al., 1999; Sullivan et al., 1997)”
From Cholesterol and matrisome pathways dysregulated in astrocytes and microglia (2022) · cites this paper as Sullivan et al., 1997
In the citing paper
“By contrast, NHE6 ablation led to glial activation and decreased plaque load in ApoeAPOE4 (Sullivan et al., 1997) and AppNL-F (Saito et al., 2014) double knockin mice.”
From NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load (2021) · cites this paper as Sullivan et al., 1997
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Metadata
- Authors
- Sullivan, P. M., Mezdour, H., Aratani, Y., Knouff, C., Najib, J., Reddick, R. L., Quarfordt, S. H., & Maeda, N.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Duke Medical Center (US)
- Corresponding author
- Maeda, Nobuyo
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1997-07
- Volume
- 272
- Issue
- 29
- Pages
- 17972-17980
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2011885704
- Cited by
- 575
- References
- 48
- Citations by year
- 2026: 17 · 2025: 26 · 2024: 25 · 2023: 39 · 2022: 28 · 2021: 32 · 2020: 31 · 2019: 21 · 2018: 12 · 2017: 20 · 2016: 27 · 2015: 22 · 2014: 29 · 2013: 21 · 2012: 29
- FWCI
- 15.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Heart, Lung, and Blood Institute (HL 42630)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- apolipoprotein E, APOE3, gene replacement, transgenic mice, hypercholesterolemia, atherosclerosis, serum lipoproteins, apolipoprotein B-100, high-fat diet, LDL receptor, cholesterol homeostasis, aortic plaque
- MeSH terms
- Alleles, Animals, Apolipoproteins E, Arteriosclerosis, Cholesterol, Diet, Atherogenic, Female, Homozygote, Humans, Hypercholesterolemia, Cholesterol, HDL, Male, Mice, Transgenic, Stem Cells, Triglycerides, Restriction Mapping, Mice, Apolipoprotein E3
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