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Differential Cellular Accumulation/Retention of Apolipoprotein E Mediated by Cell Surface Heparan Sulfate Proteoglycans

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Ji, Zhong-Sheng, Pitas, Robert E., Mahley, Robert W.·1998·Journal of Biological Chemistry
DOI 10.1074/jbc.273.22.13452
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Abstract

Isoform-specific effects of apolipoprotein E (apoE) on neurite outgrowth and the cytoskeleton are associated with higher intracellular levels of apoE3 than apoE4 in cultured neurons. The current studies, designed to determine the mechanism for the differential intracellular accumulation or retention of apoE, demonstrate that apoE3- and apoE4-containing beta-very low density lipoproteins (beta-VLDL) possess similar cell binding and internalization and delivery of cholesterol to the cells. However, as assessed by immunocytochemistry, analysis of extracted cellular proteins, or quantitation of 125I-apoE-enriched beta-VLDL, there was a 2-3-fold greater accumulation of apoE3 than apoE4 in Neuro-2a cells, fibroblasts, and hepatocytes (HepG2) after 1-2 h, and this differential was maintained for up to 48 h. ApoE2 also accumulated in Neuro-2a cells to a greater extent than apoE4. The differential effect was mediated by the apoE-enriched beta-VLDL and not by free apoE. Neither the low density lipoprotein receptor nor the low density lipoprotein receptor-related protein was responsible for the differential accumulation of apoE3 and apoE4, since cells deficient in either or both of these receptors also displayed the differential accumulation. The effect appears to be mediated primarily by cell surface heparan sulfate proteoglycans (HSPG). The retention of both apoE3 and apoE4 was markedly reduced, and the differential accumulation of apoE3 and apoE4 was eliminated both in mutant Chinese hamster ovary cells that did not express HSPG and in HSPG-expressing cells treated with heparinase. The data suggest that cell surface HSPG directly mediate the uptake of apoE-containing lipoproteins, that the differential accumulation/retention of apoE by cells is mediated via HSPG, and that there is a differential intracellular handling of the specific apoE isoforms.

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  • APOE4 has increased binding affinity (up to two-fold) for heparin and HSPG over APOE3.

    “By contrast, APOE4 has increased binding affinity (up to two-fold) for heparin and HSPG over APOE3 (refs. 32–35).”

    From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [33]

    In the ‘Metabolism of ¹²⁵I-apoE3- and ¹²⁵I-apoE4-enriched β-VLDL’ section (page unavailable), similar amounts of the two isoforms bound to wild-type CHO cells; the paper reports greater subsequent retention of apoE3. It does not report a two-fold greater apoE4 binding affinity for heparin or HSPG. The cell-binding experiment is not a direct affinity measurement, but its reported comparison runs contrary to the cited claim. (LLM, conf=0.78)

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1 of the 62 references couldn’t be matched to a known paper.

Research works printed but not linked: 10

  1. Pitas, R. E., Innerarity, T. L., Arnold, K. S., and Mahley, R. W. (1979) Proc. Natl. Acad. Sci. U. S. A. 76, 2311-2315
  2. Takahashi, S., Kawarabayasi, Y., Nakai, T., Sakai, J., and Yamamoto, T. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 9252-9256
  3. Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., and Pericak-Vance, M. A. (1993) Science 261, 921-923
  4. Saunders, A. M., Strittmatter, W. J., Schmechel, D., St. George-Hyslop, P. H., Pericak-Vance, M. A., Joo, S. H., Rosi, B. L., Gusella, J. F., Crapper- MacLachlan, D. R., Alberts, M. J., Hulette, C., Crain, B., Goldgaber, D., and Roses, A. D. (1993) Neurology 43, 1467-1472
  5. Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Jr., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., Small, G. W., Roses, A. D., Haines, J. L., and Pericak- Vance, M. A. (1994) Nat. Genet. 7, 180 -184
  6. Holtzman, D. M., Pitas, R. E., Kilbridge, J., Nathan, B., Mahley, R. W., Bu, G., and Schwartz, A. L. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 9480 -9484
  7. Kowal, R. C., Herz, J., Goldstein, J. L., Esser, V., and Brown, M. S. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 5810 -5814
  8. Strittmatter, W. J., Weisgraber, K. H., Goedert, M., Saunders, A. M., Huang, D., Corder, E. H., Dong, L.-M., Jakes, R., Alberts, M. J., Gilbert, J. R., Han, S.-H., Hulette, C., Einstein, G., Schmechel, D. E., Pericak-Vance, M. A., and Roses, A. D. (1994) Exp. Neurol. 125, 163-171
  9. Han, S.-H., Hulette, C., Saunders, A. M., Einstein, G., Pericak-Vance, M., Strittmatter, W. J., Roses, A. D., and Schmechel, D. E. (1994) Exp. Neurol. 128, 13-26
  10. Han, S.-H., Einstein, G., Weisgraber, K. H., Strittmatter, W. J., Saunders, A. M., Pericak-Vance, M., Roses, A. D., and Schmechel, D. E. (1994) J. Neuropathol. Exp. Neurol. 53, 535-544

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Authors
Ji, Z.-S., Pitas, R. E., & Mahley, R. W.
Affiliations
  • Gladstone Institutes (US)
  • University of California, San Francisco (US)
Corresponding author
Mahley, Robert W.
ORCID
Mahley, Robert W.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1998-05
Volume
273
Issue
22
Pages
13452-13460
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.273.22.13452
OpenAlex
W2002909248
Cited by
134
References
62
Citations by year
2026: 2 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2017: 3 · 2016: 1 · 2014: 6 · 2013: 2 · 2012: 2
FWCI
9.49
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01ag013619-05)
  • National Institute on Aging (AG13619)
  • National Heart, Lung, and Blood Institute (HL-41633, P01HL041633)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
Keywords
apolipoprotein E, apolipoprotein E isoforms, heparan sulfate proteoglycans, intracellular retention, beta-VLDL, APOE3, APOE ε4, APOE2, LDL receptor, low density lipoprotein receptor-related protein, heparinase, cholesterol delivery, N2a cells, hepatocytes, fibroblasts
MeSH terms
Animals, Apolipoproteins E, Cell Membrane, Endocytosis, Cricetinae, Iodine Radioisotopes, Lipoproteins, VLDL, Tumor Cells, Cultured, CHO Cells, Heparan Sulfate Proteoglycans, Mice

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