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Cited by 139Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthLipid metabolism and disorders

Impaired recycling of apolipoprotein E4 is associated with intracellular cholesterol accumulation

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Heeren, Joerg, Grewal, Thomas, Laatsch, Alexander, Becker, Nils, Rinninger, Franz, Rye, Kerry-Anne, Beisiegel, Ulrike·2004·Journal of Biological Chemistry
DOI 10.1074/jbc.m409324200
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Abstract

After internalization of triglyceride-rich lipoproteins (TRL) in hepatoma cells, TRL particles are immediately disintegrated in the early endosomal compartment. This involves the targeting of lipids and apoprotein B along the degradative pathway and the recycling of TRL-derived apoE through recycling endosomes. Re-secretion of apoE is accompanied by the concomitant association of apoE and cellular cholesterol with high-density lipoproteins (HDL). Since epidemiological data showed that apoE3 and apoE4 have differential effects on HDL metabolism, we investigated whether the intracellular processing of TRL-derived apoE4 differs from apoE3-TRL. In this study, we demonstrated by radioactive and immunofluorescence uptake experiments that cell-surface binding and internalization of TRL-derived apoE4 are increased compared with apoE3 in hepatoma cells. Pulse-chase experiments revealed that HDL-induced recycling, but not disintegration and degradation, of apoE4-enriched TRL is strongly reduced in these cells. Furthermore, impaired HDL-induced apoE4 recycling is associated with reduced cholesterol efflux. Studies performed in Tangier fibroblasts showed that apoE recycling does not depend on ATP-binding cassette transporter A1 activity. These studies provide initial evidence that impaired recycling of apoE4 could interfere with intracellular cholesterol transport and contribute to the pathophysiological lipoprotein profile observed in apoE4 homozygotes.

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  • When ApoE4 is present, the final recycling step of ApoE receptors is delayed and the process is stalled in the endosome, presumably due to the propensity of ApoE4 to form molten globules at the lower pH of the endosome.

    “when ApoE4 is present, the final recycling step is delayed and the process is stalled in the endosome, presumably due to the propensity of ApoE4 to form molten globules at the lower pH of the endosome [69, 71].”

    From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [71]

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  1. [4]4. Beisiegel, U., Weber, W., and Bengtsson-Olivecrona, G. (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 8342-8346
  2. [15]15. Huang, Y., von Eckardstein, A., Wu, S., Maeda, N., and Assmann, G. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 1834-1838
  3. [40]40. Wang, N., Lan, D., Chen, W., Matsuura, F., and Tall, A. R. (2004) Proc. Natl. Acad. Sci. U. S. A. 101, 9774-9779
  4. [41]41. Huang, Y., Liu, X. Q., Wyss-Coray, T., Brecht, W. J., Sanan, D. A., and Mahley, R. W. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 8838-8843

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Authors
Heeren, J., Grewal, T., Laatsch, A., Becker, N., Rinninger, F., Rye, K.-A., & Beisiegel, U.
Affiliations
  • UNSW Sydney (AU)
  • University Medical Center Hamburg-Eppendorf (DE)
  • The Heart Research Institute (AU)
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2004-12
Volume
279
Issue
53
Pages
55483-55492
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m409324200
OpenAlex
W2143666437
Cited by
139
References
54
Citations by year
2026: 3 · 2025: 6 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 11 · 2017: 11 · 2016: 4 · 2015: 4 · 2014: 11 · 2013: 3 · 2012: 8
FWCI
5.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
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
APOE ε4, apolipoprotein E3, triglyceride-rich lipoproteins, HDL cholesterol, intracellular cholesterol accumulation, cholesterol efflux, apolipoprotein B, ABCA1, Tangier disease, hepatoma cells, lipoprotein metabolism
MeSH terms
Alleles, Apolipoproteins B, Apolipoproteins E, Cell Line, Cell Membrane, Cholesterol, Electrophoresis, Polyacrylamide Gel, Fibroblasts, Carcinoma, Hepatocellular, Homozygote, Humans, Ligands, Lipids, Lipoproteins, HDL, Microscopy, Fluorescence, Endosomes, Time Factors, Triglycerides, Blotting, Western, ATP-Binding Cassette Transporters, Protein Isoforms, Reverse Transcriptase Polymerase Chain Reaction, Cell Line, Tumor, Lipid Metabolism, Apolipoprotein E4, ATP Binding Cassette Transporter 1

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