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Papers In Press, published online ahead of print May 16, 2004
J. Lipid Res., doi:10.1194/jlr.M400104-JLR200
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Pathology Dept., Vanderbilt University School of Medicine, Nashville, TN 37232-2561
Corresponding Author: larry.swift{at}vanderbilt.edu
A portion of apolipoprotein (apo) E internalized by hepatocytes is spared degradation and is recycled. To investigate the intracellular routing of recycling apoE, we studied primary hepatocyte cultures from LDL receptor deficient mice and mice deficient in receptor associated protein (a model of depressed expression of LDL receptor related protein, LRP). After incubation with human VLDL containing 125I-labeled human recombinant apoE3, intact labeled apoE appeared in the media in a time-dependent fashion. Approximately 30 % of the internalized intact apoE was recycled after 4 h. In addition, the amino-terminal 22 kDa fragment of apoE comprised approximately 10% of the radioactivity in the starting material but nearly 50% of radioactivity in the resecreted material, demonstrating that this apoE domain contains sufficient sequence to recycle. Because the apoE fragment has reduced affinity for lipoproteins, these data suggest that the pathway of apoE recycling is linked to the ability of apoE to bind directly to a recycling receptor. Finally, apoE was found to recycle equally well in the presence of brefeldin A, a fungal metabolite that blocks trafficking from the endoplasmic reticulum and leads to dissolution of the Golgi apparatus. Our studies demonstrate that apoE recycling occurs (1) in the absence of the LDL receptor or under conditions of markedly reduced LRP expression; (2) when apoE lacks the carboxyl-terminal domain, which allows binding to the lipoprotein; and (3) in the absence of an intact Golgi apparatus. We conclude that apoE recycling occurs through multiple redundant pathways.
Revised on May 13, 2004
Accepted on May 13, 2004
The recycling of apolipoprotein E and its amino-terminal 22 kDa fragment: Evidence for multiple redundant pathways
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