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Journal of Lipid Research, Vol. 45, 1546-1554, August 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

The recycling of apolipoprotein E and its amino-terminal 22 kDa fragment

Monica H. Farkas^*, Karl H. Weisgraber^**,, Virginia L. Shepherd^*, MacRae F. Linton^1,,, Sergio Fazio^1,*, and Larry L. Swift^1,*

^* Departments of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232
Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232
Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232
^** Gladstone Institute of Cardiovascular Diseases, University of California, San Francisco, CA 94141
Cardiovascular Research Institute, and the Department of Pathology, University of California, San Francisco, CA 94141

¹ To whom correspondence should be addressed. e-mail: larry.swift{at}vanderbilt.edu (L.L.S.); sergio.fazio{at}vanderbilt.edu (S.F.); macrae.linton{at}vanderbilt.edu (M.F.L.)

A portion of apolipoprotein E (apoE) internalized by hepatocytes is spared degradation and is recycled. To investigate the intracellular routing of recycling apoE, 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)] were incubated with human VLDL containing ¹²⁵I-labeled human recombinant apoE3. Approximately 30% of the internalized intact apoE was recycled after 4 h. The N-terminal 22 kDa fragment of apoE was also resecreted, demonstrating that this apoE domain contains sufficient sequence to recycle. The 22 kDa fragment has reduced affinity for lipoproteins, suggesting that 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 drug that blocks transport from the endoplasmic reticulum and leads to collapse of the Golgi stacks.

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.

Supplementary key words very low density lipoprotein • low density lipoprotein • LDL receptor • receptor-associated protein • LDL receptor-related protein • brefeldin A

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