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Abnormal in vivo metabolism of apolipoprotein E4 in humans.
Open accessAbstract
Apolipoprotein E (apoE) is important in modulating the catabolism of remnants of triglyceride-rich lipoprotein particles. It is a polymorphic protein with the three common alleles coding for apoE2, apoE3, and apoE4. ApoE3 is considered the normal isoform, while apoE4 is associated both with hypercholesterolemia and type V hyperlipoproteinemia. We quantitated the kinetics of metabolism of apoE4 in 19 normolipidemic apoE3 homozygotes and 1 normolipidemic apoE4 homozygote, and compared this with the metabolism of apoE3 in 12 normolipidemic apoE3 homozygotes. In the apoE3 homozygous subjects, apoE4 was catabolized twice as fast as apoE3, with a mean plasma residence time of 0.37 +/- 0.01 d (+/- SEM) and 0.73 +/- 0.05 (P less than 0.001), respectively. When plasma was fractionated into the lipoprotein subclasses, the greatest amount of labeled apoE4 was present on very low density lipoproteins, while the largest fraction of labeled apoE3 was associated with high density lipoproteins. The plasma apoE concentration was decreased in an apoE4 homozygote compared with the apoE3 homozygotes (3.11 mg/dl vs. 4.83 +/- 0.35 mg/dl). The reduced apoE4 concentration was entirely due to a decreased apoE4 residence time in the apoE4 homozygote (0.36 d vs. 0.73 +/- 0.05 d for apoE3 in apoE3 homozygotes). These results indicate that apoE4 is kinetically different than apoE3, and suggest that the presence of apoE4 in hypercholesterolemic and type V hyperlipoproteinemic individuals may play an important pathophysiological role in the development of these dyslipoproteinemias.
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“In humans and animal models, apoE genotype is correlated with apoE protein levels in plasma, with 2 showing the highest protein levels and 4 the lowest (Eto et al., 1986;Gregg et al., 1986;Raffai et al., 2001) (Fig. 2).”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Gregg et al., 1986
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“where ApoE4 is catabolized twice as fast as ApoE3 [15].”
From In Vivo Human Apolipoprotein E Isoform Fractional Turnover Rates in the CNS (2012) · cites this paper as [15]
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“Despite near-normal receptor affinity of apoE4 the amino acid change leads to differences in distribution in lipoprotein classes: apoE3 shows preference for high density lipoprotein (HDL) particles, whereas apoE4 shows preference for very low density lipoprotein (VLDL) particles [38].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [38]
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“Early work showed that, in the blood, APOE4 preferentially associates with VLDL, whereas APOE3 displays a preference for HDL (Gregg et al., 1986;Steinmetz et al., 1989;Weisgraber, 1990).”
From Isoform- and cell-state-specific lipidation of ApoE in astrocytes (2022) · cites this paper as Gregg et al., 1986
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Self-citation
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Metadata
- Authors
- Gregg, R. E., Zech, L. A., Schaefer, E. J., Stark, D., Wilson, D., & Brewer, H. B.
- Affiliations
- Tufts University (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1986-09-01
- Volume
- 78
- Issue
- 3
- Pages
- 815-821
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC423680
- OpenAlex
- W1990170200
- Cited by
- 345
- References
- 27
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 8 · 2018: 7 · 2017: 6 · 2016: 6 · 2015: 3 · 2014: 4 · 2013: 9 · 2012: 8
- FWCI
- 11.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- NIH Clinical Center
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- APOE ε4, apolipoprotein E3, APOE polymorphism, plasma residence time, VLDL, high-density lipoprotein, type V hyperlipoproteinemia, hypercholesterolemia, dyslipoproteinemia
- MeSH terms
- Adolescent, Adult, Apolipoproteins E, Female, Homozygote, Humans, Hypercholesterolemia, Hyperlipoproteinemia Type V, Iodine Radioisotopes, Kinetics, Lipoproteins, Lipoproteins, HDL, Lipoproteins, LDL, Lipoproteins, VLDL, Male, Phenotype, Apolipoprotein E3, Apolipoprotein E4, Lipoproteins, IDL
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