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J. Biol. Chem., Vol. 283, Issue 17, 11374-11381, April 25, 2008

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Regulation of ApoB Secretion by the Low Density Lipoprotein Receptor Requires Exit from the Endoplasmic Reticulum and Interaction with ApoE or ApoB^*

From the Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706

Apolipoprotein B (apoB) is required for the hepatic assembly and secretion of very low density lipoprotein (VLDL). The LDL receptor (LDLR) promotes post-translational degradation of apoB and thereby reduces VLDL particle secretion. We investigated the trafficking pathways and ligand requirements for the LDLR to promote degradation of apoB. We first tested whether the LDLR drives apoB degradation in an endoplasmic reticulum (ER)-associated pathway. Primary mouse hepatocytes harboring an ethyl-nitrosourea-induced, ER-retained mutant LDLR secreted comparable levels of apoB with LDLR-null hepatocytes, despite reduced secretion from cells expressing the wild-type LDLR. Additionally, treatment of cells with brefeldin A inhibited LDLR-dependent degradation. However, this rescue was reversible, and degradation of apoB occurred upon removal of brefeldin A. To characterize the lipoprotein reuptake pathway of degradation, we employed an LDLR mutant defective in constitutive endocytosis and internalization of apoB. This mutant was as effective in reducing apoB secretion as the wild-type LDLR. However, the effect was dependent on apolipoprotein E (apoE) as only the wild-type LDLR, and not the endocytic mutant, reduced apoB secretion in apoE-null cells. Treatment with heparin rescued a pool of apoB in cells expressing the endocytic mutant, indicating that reuptake of VLDL via apoE still occurs with this mutant. Finally, an LDLR mutant defective in binding apoB but not apoE reduced apoB secretion in an apoE-dependent manner. Together, these data suggest that the LDLR directs apoB to degradation in a post-ER compartment. Furthermore, the reuptake mechanism of degradation occurs via internalization of apoB through a constitutive endocytic pathway and apoE through a ligand-dependent pathway.

Received for publication, December 22, 2007 , and in revised form, February 5, 2008.

^* This project was funded by NHLBI, National Institutes of Health Grant HL56593. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ Supported by the National Institutes of Health and National Institute on Aging Grant T32 AG20013, Sanjay Asthana, Principal Investigator, and the National Institutes of Health, National Research Service Award T32 HL07936, from the University of Wisconsin-Madison Cardiovascular Research Center.

² To whom correspondence should be addressed: 433 Babcock Dr., Madison, WI 53706-1544. Tel.: 608-262-1372; Fax: 608-263-9609; E-mail: adattie{at}wisc.edu.

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