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J. Biol. Chem., Vol. 282, Issue 27, 19453-19462, July 6, 2007

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Golgi-associated Maturation of Very Low Density Lipoproteins Involves Conformational Changes in Apolipoprotein B, but Is Not Dependent on Apolipoprotein E^*

Viktoria Gusarova, Jeongmin Seo, Mara L. Sullivan, Simon C. Watkins, Jeffrey L. Brodsky^¶, and Edward A. Fisher¹

From the Departments of Medicine (Leon Charney Division of Cardiology) and Cell Biology and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York 10016, the Center for Biological Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, and the ^¶Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

The major protein component in secreted very low density lipoproteins (VLDL) is apoB, and it is established that these particles can reach sizes approaching 100 nm. We previously employed a cell-free system to investigate the nature of the vesicles in which this large cargo exits the endoplasmic reticulum (ER) (Gusarova, V., Brodsky, J. L., and Fisher, E. A. (2003) J. Biol. Chem. 278, 48051–48058). We found that apoB-containing lipoproteins exit the ER as dense lipid-protein complexes regardless of the final sizes of the particles and that further expansion occurs via post-ER lipidation. Here, we focused on maturation in the Golgi apparatus. In three separate approaches, we found that VLDL maturation (as assessed by changes in buoyant density) was associated with conformational changes in apoB. In addition, as the size of VLDL expanded, apoE concentrated in a subclass of Golgi microsomes or Golgi-derived vesicles that co-migrated with apoB-containing microsomes or vesicles, respectively. A relationship between apoB and apoE was further confirmed in co-localization studies by immunoelectron microscopy. These combined results are consistent with previous suggestions that apoE is required for VLDL maturation. To our surprise, however, we observed robust secretion of mature VLDL when apoE synthesis was inhibited in either rat hepatoma cells or apoE^–/– mouse primary hepatocytes. We conclude that VLDL maturation in the Golgi involves apoB conformational changes and that the expansion of the lipoprotein does not require apoE; rather, the increase in VLDL surface area favors apoE binding.

Received for publication, January 17, 2007 , and in revised form, May 11, 2007.

^* This work was supported by National Institutes of Health Grant HL58541 (to E. A. F. and J. L. B.). 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.

¹ To whom correspondence should be addressed: Dept. of Medicine, New York University School of Medicine, 522 First Ave., Smilow-8, New York, NY 10016. Tel.: 212-263-6631; Fax: 212-263-6632; E-mail: edward.fisher{at}med.nyu.edu.

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