HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ji, Z.-S. Articles by Mahley, R. W. Search for Related Content PubMed PubMed Citation Articles by Ji, Z.-S. Articles by Mahley, R. W.

J Biol Chem, Vol. 273, Issue 22, 13452-13460, May 29, 1998

Differential Cellular Accumulation/Retention of Apolipoprotein E Mediated by Cell Surface Heparan Sulfate Proteoglycans
APOLIPOPROTEINS E3 AND E2 GREATER THAN E4

Zhong-Sheng Ji, Robert E. Pitas^§, and Robert W. Mahley^§¶

From the  Gladstone Institute of Cardiovascular Disease, Cardiovascular Research Institute, and the Departments of ^§ Pathology and ^¶ Medicine, University of California, San Francisco, California 94141-9100

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 -very low density lipoproteins (-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 -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 -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.

---

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

This article has been cited by other articles:

				D. Fan, S. Qiu, C. D. Overton, P. G. Yancey, L. L. Swift, W. G. Jerome, M. F. Linton, and S. Fazio Impaired Secretion of Apolipoprotein E2 from Macrophages J. Biol. Chem., May 4, 2007; 282(18): 13746 - 13753. [Abstract] [Full Text] [PDF]

				M. Bazrgar, M. Karimi, F. Peiravian, and M. Fathzadeh Apolipoprotein E gene polymorphism and left ventricular function in Iranian patients with thalassemia major Haematologica, February 1, 2007; 92(2): 256 - 257. [Abstract] [Full Text] [PDF]

				N. A. Braun, P. J. Mohler, K. H. Weisgraber, A. H. Hasty, M. F. Linton, P. G. Yancey, Y. R. Su, S. Fazio, and L. L. Swift Intracellular trafficking of recycling apolipoprotein E in Chinese hamster ovary cells J. Lipid Res., June 1, 2006; 47(6): 1176 - 1186. [Abstract] [Full Text] [PDF]

				C. C. Hsu, W. H. L. Kao, J. Coresh, J. S. Pankow, J. Marsh-Manzi, E. Boerwinkle, and M. S. Bray Apolipoprotein E and Progression of Chronic Kidney Disease JAMA, June 15, 2005; 293(23): 2892 - 2899. [Abstract] [Full Text] [PDF]

				D. E. Dove, M. F. Linton, and S. Fazio ApoE-mediated cholesterol efflux from macrophages: separation of autocrine and paracrine effects Am J Physiol Cell Physiol, March 1, 2005; 288(3): C586 - C592. [Abstract] [Full Text] [PDF]

				M. Futamura, P. Dhanasekaran, T. Handa, M. C. Phillips, S. Lund-Katz, and H. Saito Two-step Mechanism of Binding of Apolipoprotein E to Heparin: IMPLICATIONS FOR THE KINETICS OF APOLIPOPROTEIN E-HEPARAN SULFATE PROTEOGLYCAN COMPLEX FORMATION ON CELL SURFACES J. Biol. Chem., February 18, 2005; 280(7): 5414 - 5422. [Abstract] [Full Text] [PDF]

				M. H. Farkas, K. H. Weisgraber, V. L. Shepherd, M. F. Linton, S. Fazio, and L. L. Swift The recycling of apolipoprotein E and its amino-terminal 22 kDa fragment: evidence for multiple redundant pathways J. Lipid Res., August 1, 2004; 45(8): 1546 - 1554. [Abstract] [Full Text] [PDF]

				J. Raber Androgens, ApoE, and Alzheimer's Disease Sci. Aging Knowl. Environ., March 17, 2004; 2004(11): re2 - re2. [Abstract] [Full Text] [PDF]

				R. J. Havel and R. L. Hamilton Hepatic Catabolism of Remnant Lipoproteins: Where the Action Is Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 213 - 215. [Full Text] [PDF]

				H. Saito, P. Dhanasekaran, D. Nguyen, F. Baldwin, K. H. Weisgraber, S. Wehrli, M. C. Phillips, and S. Lund-Katz Characterization of the Heparin Binding Sites in Human Apolipoprotein E J. Biol. Chem., April 18, 2003; 278(17): 14782 - 14787. [Abstract] [Full Text] [PDF]

				M. H. Farkas, L. L. Swift, A. H. Hasty, M. F. Linton, and S. Fazio The Recycling of Apolipoprotein E in Primary Cultures of Mouse Hepatocytes. EVIDENCE FOR A PHYSIOLOGIC CONNECTION TO HIGH DENSITY LIPOPROTEIN METABOLISM J. Biol. Chem., March 7, 2003; 278(11): 9412 - 9417. [Abstract] [Full Text] [PDF]

				E. Paradis, S. Clement, P. Julien, and M. R. Ven Murthy Lipoprotein Lipase Affects the Survival and Differentiation of Neural Cells Exposed to Very Low Density Lipoprotein J. Biol. Chem., March 7, 2003; 278(11): 9698 - 9705. [Abstract] [Full Text] [PDF]

				M. Hara, T. Matsushima, H. Satoh, N. Iso-o, H. Noto, M. Togo, S. Kimura, Y. Hashimoto, and K. Tsukamoto Isoform-Dependent Cholesterol Efflux From Macrophages by Apolipoprotein E Is Modulated by Cell Surface Proteoglycans Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 269 - 274. [Abstract] [Full Text] [PDF]

				M. Buttini, G.-Q. Yu, K. Shockley, Y. Huang, B. Jones, E. Masliah, M. Mallory, T. Yeo, F. M. Longo, and L. Mucke Modulation of Alzheimer-Like Synaptic and Cholinergic Deficits in Transgenic Mice by Human Apolipoprotein E Depends on Isoform , Aging, and Overexpression of Amyloid beta Peptides But Not on Plaque Formation J. Neurosci., December 15, 2002; 22(24): 10539 - 10548. [Abstract] [Full Text] [PDF]

				A. E. Mullick, R. J. Deckelbaum, I. J. Goldberg, M. Al-Haideri, and J. C. Rutledge Apolipoprotein E and Lipoprotein Lipase Increase Triglyceride-Rich Particle Binding but Decrease Particle Penetration in Arterial Wall Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 2080 - 2085. [Abstract] [Full Text] [PDF]

				L. Nadav, A. Eldor, O. Yacoby-Zeevi, E. Zamir, I. Pecker, N. Ilan, B. Geiger, I. Vlodavsky, and B.-Z. Katz Activation, processing and trafficking of extracellular heparanase by primary human fibroblasts J. Cell Sci., May 15, 2002; 115(10): 2179 - 2187. [Abstract] [Full Text] [PDF]

				A. K. Stannard, D. R. Riddell, S. M. Sacre, A. D. Tagalakis, C. Langer, A. von Eckardstein, P. Cullen, T. Athanasopoulos, G. Dickson, and J. S. Owen Cell-derived Apolipoprotein E (ApoE) Particles Inhibit Vascular Cell Adhesion Molecule-1 (VCAM-1) Expression in Human Endothelial Cells J. Biol. Chem., November 30, 2001; 276(49): 46011 - 46016. [Abstract] [Full Text] [PDF]

				J. Heeren, T. Grewal, S. Jackle, and U. Beisiegel Recycling of Apolipoprotein E and Lipoprotein Lipase through Endosomal Compartments in Vivo J. Biol. Chem., November 2, 2001; 276(45): 42333 - 42338. [Abstract] [Full Text] [PDF]

				C. LYNCH and W. MOBLEY Comprehensive Theory of Alzheimer's Disease: The Effects of Cholesterol on Membrane Receptor Trafficking Ann. N.Y. Acad. Sci., December 1, 2000; 924(1): 104 - 111. [Abstract] [Full Text] [PDF]

				K. C-W. Yu, Y. Jiang, W. Chen, and A. D. Cooper Rapid initial removal of chylomicron remnants by the mouse liver does not require hepatically localized apolipoprotein E J. Lipid Res., November 1, 2000; 41(11): 1715 - 1727. [Abstract] [Full Text]

				F. K. Welty, A. H. Lichtenstein, P. H. R. Barrett, J. L. Jenner, G. G. Dolnikowski, and E. J. Schaefer Effects of ApoE Genotype on ApoB-48 and ApoB-100 Kinetics With Stable Isotopes in Humans Arterioscler. Thromb. Vasc. Biol., July 1, 2000; 20(7): 1807 - 1810. [Abstract] [Full Text] [PDF]

				P. C. N. Rensen, M. C. Jong, L. C. van Vark, H. van der Boom, W. L. Hendriks, T. J. C. van Berkel, E. A. L. Biessen, and L. M. Havekes Apolipoprotein E Is Resistant to Intracellular Degradation in Vitro and in Vivo. EVIDENCE FOR RETROENDOCYTOSIS J. Biol. Chem., March 17, 2000; 275(12): 8564 - 8571. [Abstract] [Full Text] [PDF]

				L. Paka, I. J. Goldberg, J. C. Obunike, S. Y. Choi, U. Saxena, I. D. Goldberg, and S. Pillarisetti Perlecan Mediates the Antiproliferative Effect of Apolipoprotein E on Smooth Muscle Cells. AN UNDERLYING MECHANISM FOR THE MODULATION OF SMOOTH MUSCLE CELL GROWTH? J. Biol. Chem., December 17, 1999; 274(51): 36403 - 36408. [Abstract] [Full Text] [PDF]

				R. W. Mahley, Y. Huang, and S. C. Rall , Jr. Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes J. Lipid Res., November 1, 1999; 40(11): 1933 - 1949. [Abstract] [Full Text]

				K. Tsukamoto, R. Tangirala, S. H. Chun, E. Pure, and D. J. Rader Rapid Regression of Atherosclerosis Induced by Liver-Directed Gene Transfer of ApoE in ApoE-Deficient Mice Arterioscler. Thromb. Vasc. Biol., September 1, 1999; 19(9): 2162 - 2170. [Abstract] [Full Text] [PDF]

				M. Buttini, M. Orth, S. Bellosta, H. Akeefe, R. E. Pitas, T. Wyss-Coray, L. Mucke, and R. W. Mahley Expression of Human Apolipoprotein E3 or E4 in the Brains of Apoe-/- Mice: Isoform-Specific Effects on Neurodegeneration J. Neurosci., June 15, 1999; 19(12): 4867 - 4880. [Abstract] [Full Text] [PDF]

				R. B. DeMattos, F. E. Thorngate, and D. L. Williams A Test of the Cytosolic Apolipoprotein E Hypothesis Fails to Detect the Escape of Apolipoprotein E from the Endocytic Pathway into the Cytosol and Shows that Direct Expression of Apolipoprotein E in the Cytosol is Cytotoxic J. Neurosci., April 1, 1999; 19(7): 2464 - 2473. [Abstract] [Full Text] [PDF]

				S. Fazio, M. F. Linton, A. H. Hasty, and L. L. Swift Recycling of Apolipoprotein E in Mouse Liver J. Biol. Chem., March 19, 1999; 274(12): 8247 - 8253. [Abstract] [Full Text] [PDF]

				R. W. Mahley and Z.-S. Ji Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E J. Lipid Res., January 1, 1999; 40(1): 1 - 16. [Abstract] [Full Text]

				R. K. Tangirala, D. Pratico, G. A. FitzGerald, S. Chun, K. Tsukamoto, C. Maugeais, D. C. Usher, E. Pure, and D. J. Rader Reduction of Isoprostanes and Regression of Advanced Atherosclerosis by Apolipoprotein E J. Biol. Chem., January 5, 2001; 276(1): 261 - 266. [Abstract] [Full Text] [PDF]