Apo E structure determines VLDL clearance and atherosclerosis risk in mice

Knouff, Christopher; Hinsdale, Myron E.; Mezdour, Hafid; Altenburg, Michael K.; Watanabe, Masahiko; Quarfordt, Steven H.; Sullivan, Patrick M.; Maeda, Nobuyo

doi:10.1172/jci6172

Cited by 324Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthLipid metabolism and disorders

Apo E structure determines VLDL clearance and atherosclerosis risk in mice

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Knouff, Christopher, Hinsdale, Myron E., Mezdour, Hafid, Altenburg, Michael K., Watanabe, Masahiko, Quarfordt, Steven H., Sullivan, Patrick M., Maeda, Nobuyo·1999·Journal of Clinical Investigation

DOI 10.1172/jci6172PMC PMC408371

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Abstract

We have generated mice expressing the human apo E4 isoform in place of the endogenous murine apo E protein and have compared them with mice expressing the human apo E3 isoform. Plasma lipid and apolipoprotein levels in the mice expressing only the apo E4 isoform (4/4) did not differ significantly from those in mice with the apo E3 isoform (3/3) on chow and were equally elevated in response to increased lipid and cholesterol in their diet. However, on all diets tested, the 4/4 mice had approximately twice the amount of cholesterol, apo E, and apo B-48 in their VLDL as did 3/3 mice. The 4/4 VLDL competed with human LDL for binding to the human LDL receptor slightly better than 3/3 VLDL, but the VLDL clearance rate in 4/4 mice was half that in 3/3 mice. On an atherogenic diet, there was a trend toward greater atherosclerotic plaque size in 4/4 mice compared with 3/3 mice. These data, together with our earlier observations in wild-type and human APOE*2-replacement mice, demonstrate a direct and highly significant correlation between VLDL clearance rate and mean atherosclerotic plaque size. Therefore, differences solely in apo E protein structure are sufficient to cause alterations in VLDL residence time and atherosclerosis risk in mice.

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The human apoE-TR homozygous male mice express human APOE3 or APOE4 under the mouse APOE promoter, replacing the endogenous mouse APOE.
“The human apoE-TR homozygous male mice with the C57BL/6J background were purchased from Taconic (www.taconic.com), in which the expression of human APOE3 or APOE4 is controlled by the mouse APOE promoter, replacing the endogenous mouse APOE [26].”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [26]
APOE TR mice were previously generated by removing and replacing the endogenous mouse Apoe gene with the human APOE gene.
“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 [52]

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Authors: Knouff, C., Hinsdale, M. E., Mezdour, H., Altenburg, M. K., Watanabe, M., Quarfordt, S. H., Sullivan, P. M., & Maeda, N.
Affiliations: University of North Carolina at Chapel Hill (US)
Institut Pasteur de Lille (FR)
Hokkaido University (JP)
Duke University (US)
Corresponding author: Maeda, Nobuyo
ORCID: Hinsdale, Myron E.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1999-06-01
Volume: 103
Issue: 11
Pages: 1579-1586
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci6172
PMC: PMC408371
OpenAlex: W1979536020
Cited by: 324
References: 7
Citations by year: 2026: 15 · 2025: 14 · 2024: 12 · 2023: 24 · 2022: 21 · 2021: 20 · 2020: 21 · 2019: 17 · 2018: 6 · 2017: 12 · 2016: 16 · 2015: 13 · 2014: 8 · 2013: 10 · 2012: 10
FWCI: 7.48
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
UNC Libraries
Funders: National Institutes of Health
National Heart, Lung, and Blood Institute (HL 42630, R37HL042630, R01HL042630)
National Cancer Institute (P30CA016086)
National Center for Research Resources (RR 00111, K01RR000111)
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: apolipoprotein E, APOE ε4, APOE3, VLDL clearance, atherosclerosis, LDL receptor binding, apoB-48, plasma lipids, transgenic mice, atherogenic diet
MeSH terms: Animals, Aorta, Apolipoproteins E, Arteriosclerosis, Humans, Lipoproteins, VLDL, Mice, Inbred C57BL, Risk Factors, Mice, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2

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Apo E structure determines VLDL clearance and atherosclerosis risk in mice

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