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Journal of Lipid Research, Vol 38, 1070-1084, Copyright © 1997 by Lipid Research, Inc.
PC Rensen, N Herijgers, MH Netscher, SC Meskers, M van Eck and TJ van Berkel
Apolipoprotein E (apoE) is an important determinant for the uptake of
triglyceride-rich emulsions and lipoproteins by the liver, and exerts
affinity for both the LDL receptor (LDLr) and a distinct liver-specific
recognition site. Our current aim was to assess the mechanism underlying
the receptor-specificity of apoE-carrying lipoproteins. Triglyceride-rich
emulsions were synthesized, with mean sizes of 50, 80, and 150 nm. These
fractions efficiently acquired apoE from rat serum, and were processed by
LPL in vivo with a similar efficiency. Upon injection of the
[5H]cholesteryl oleate-labeled emulsions into rats, the liver association
rate was positively correlated with particle size (24 +/- 2%, 54 +/- 1%,
and 64 +/- 3% of the injected dose at 20 min after injection, respectively)
and the liver uptake was predominantly exerted by parenchymal cells. The
role of the LDLr in emulsion clearance was established in wild-type versus
LDLr knockout mice. In the absence of the LDLr, an 8-fold increased serum
half-life was observed for the small emulsion, concomitant with a 6- and
15-fold decreased uptake by the liver and adrenals at 60 min after
injection, respectively. In contrast, the in vivo behavior of the large
emulsion was independent of the LDLr. Both the ratio of apoE:C on the
emulsions upon serum incubation and the alpha-helical content of apoE were
inversely correlated with particle size, indicating that these factors may
be involved in the emulsion size-dependent receptor specificity in vivo. It
is concluded that the contribution of the LDLr to the apoE- mediated
clearance of emulsions by the liver and adrenals strongly increases with
decreasing particle size, while large particles initially associate with a
distinct liver-specific recognition site. As these emulsions mimic
chylomicrons, we anticipate that the apoE- dependent metabolic behavior of
chylomicrons (remnants) is largely dependent on their size.
ARTICLES
Particle size determines the specificity of apolipoprotein E-containing triglyceride-rich emulsions for the LDL receptor versus hepatic remnant receptor in vivo
Division of Biopharmaceutics, Leiden-Amsterdam Center for Drug Research, University of Leiden, Sylvius Laboratories, The Netherlands.
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 A. J. Versluis, E. T. Rump, P. C. N. Rensen, T. J. C. van Berkel, and M. K. Bijsterbosch Stable Incorporation of a Lipophilic Daunorubicin Prodrug into Apolipoprotein E-Exposing Liposomes Induces Uptake of Prodrug via Low-Density Lipoprotein Receptor in Vivo J. Pharmacol. Exp. Ther., April 1, 1999; 289(1): 1 - 7. [Abstract] [Full Text]
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H. E. de Vries, A. C. E. Moor, T. M.A.R. Dubbelman, T. J. C. van Berkel, and J. Kuiper Oxidized Low-Density Lipoprotein as a Delivery System for Photosensitizers: Implications for Photodynamic Therapy of Atherosclerosis J. Pharmacol. Exp. Ther., April 1, 1999; 289(1): 528 - 534. [Abstract] [Full Text]
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K. W. van Dijk, B. J. M. van Vlijmen, H. B. van't Hof, A. van der Zee, S. Santamarina-Fojo, T. J.C. van Berkel, L. M. Havekes, and M. H. Hofker In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE J. Lipid Res., February 1, 1999; 40(2): 336 - 344. [Abstract] [Full Text]
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N. Mekki, M. A. Christofilis, M. Charbonnier, C. Atlan-Gepner, C. Defoort, C. Juhel, P. Borel, H. Portugal, A. M. Pauli, B. Vialettes, et al. Influence of Obesity and Body Fat Distribution on Postprandial Lipemia and Triglyceride-Rich Lipoproteins in Adult Women J. Clin. Endocrinol. Metab., January 1, 1999; 84(1): 184 - 191. [Abstract] [Full Text]
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 P. C. N. Rensen, R. M. Schiffelers, A. J. Versluis, M. K. Bijsterbosch, M. E. M. J. Van Kuijk-Meuwissen, and T. J. C. Van Berkel Human Recombinant Apolipoprotein E-Enriched Liposomes Can Mimic Low-Density Lipoproteins as Carriers for the Site-Specific Delivery of Antitumor Agents Mol. Pharmacol., September 1, 1997; 52(3): 445 - 455. [Abstract] [Full Text]
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P. C. N. Rensen, L. A. J. M. Sliedregt, M. Ferns, E. Kieviet, S. M. W. van Rossenberg, S. H. van Leeuwen, T. J. C. van Berkel, and E. A. L. Biessen Determination of the Upper Size Limit for Uptake and Processing of Ligands by the Asialoglycoprotein Receptor on Hepatocytes in Vitro and in Vivo J. Biol. Chem., September 28, 2001; 276(40): 37577 - 37584. [Abstract] [Full Text] [PDF]
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