Characterization of apolipoprotein E7 (Glu244→Lys, Glu245→Lys), a mutant apolipoprotein E associated with hyperlipidemia and atherosclerosis
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Previously, a mutant apolipoprotein (apo) E, apolipoprotein E7 (Glu(244)-->Lys, Glu(245)--->Lys), has been identified in association with hyperlipidemia and atherosclerosis. To investigate the effects of its structural changes on lipoprotein metabolisms and its correlation with atherosclerosis, we characterized this mutant apoE with respect to its receptor-binding, heparin-binding, and lipoprotein association. In a competitive binding assay, apoE7. dimyristoylphosphatidylcholine displayed a defective binding to the low density lipoprotein (LDL) receptor. The concentration of apoE7 required for 50% displacement of (125)I-labeled LDL was 0.223 microg/ml, while that for apoE3 was 0.048 microg/ml. ApoE7 possesses only 23% of normal binding activity. To investigate the lipoprotein preference of apoE7, we determined the relative amounts of apoE7 in plasma lipoprotein fractions obtained by ultracentrifugation or gel filtration. Like human apoE4, apoE7 was preferentially associated with the very low density lipoproteins (VLDL). For determination of heparin-binding activity, apoVLDL was applied to a heparin-Sepharose affinity column and the bound materials were eluted with a salt gradient. The apoE7 was eluted at a higher NaCl concentration (157 mm) than apoE3 (126 mm), indicating that this mutant has a higher affinity for heparin than does apoE3. While the reduced receptor-binding activity indicates delayed clearance of the triglyceride-rich lipoproteins, the preferential association of apoE7 with larger-size lipoproteins and the stronger interaction with heparin may compensate, to some extent, for the delayed clearance of triglyceride-rich lipoproteins. The strong interaction with proteoglycans in the arterial wall seems to be one of the possible explanations for the association of apoE7 with atherosclerosis.-Yamamura, T., L-M. Dong, and A. Yamamoto. Characterization of apolipoprotein E7 (Glu(244)-->Lys, Glu(245)--->Lys), a mutant apolipoprotein E associated with hyperlipidemia and atherosclerosis.
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This substitution reduces the binding affinity of the ε7 isoform to the LDL receptor (LDLR) and increases its affinity for heparin.
“This substitution reduces the binding affinity of the ε7 isoform to the LDL receptor (LDLR) and increases its affinity for heparin. 38”
From Association of rare <i>APOE</i> missense variants with Alzheimer's disease in the Japanese population (2025) · cites this paper as [38]
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- Authors
- Yamamura, T., Dong, L.-M., & Yamamoto, A.
- Affiliations
- National Cerebral and Cardiovascular Center (JP)
- Corresponding author
- Yamamura, Taku
- ORCID
- Yamamoto, Akira
- Venue
- Journal of Lipid Research
- Publisher
- Elsevier BV
- Published
- 1999-02
- Volume
- 40
- Issue
- 2
- Pages
- 253-259
- ISSN
- 0022-2275 (ISSN-L)
- OpenAlex
- W1831090094
- Cited by
- 25
- References
- 7
- Citations by year
- 2025: 1 · 2023: 8 · 2022: 2 · 2021: 1 · 2019: 1 · 2018: 1 · 2017: 2 · 2012: 2
- FWCI
- 1.40
- 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
- Institute for Protein Research, Osaka University
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- apolipoprotein E, hyperlipidemia, atherosclerosis, LDL receptor binding, heparin binding, VLDL, lipoprotein metabolism, proteoglycans, arterial wall, apolipoprotein E3
- MeSH terms
- Apolipoproteins E, Arteriosclerosis, Binding, Competitive, Cells, Cultured, Cholesterol, Chromatography, Gel, Fibroblasts, Heparin, Humans, Hyperlipidemias, Iodine Radioisotopes, Isoelectric Focusing, Lipoproteins, Phenotype, Protein Binding, Receptors, LDL, Triglycerides, Point Mutation, Apolipoprotein E3
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