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J. Biol. Chem., Vol. 278, Issue 48, 48051-48058, November 28, 2003

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Apolipoprotein B100 Exit from the Endoplasmic Reticulum (ER) Is COPII-dependent, and Its Lipidation to Very Low Density Lipoprotein Occurs Post-ER^*

Viktoria Gusarova, Jeffrey L. Brodsky, and Edward A. Fisher¶

From the Departments of Medicine and Biochemistry/Molecular Biology and The Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York 10029 and Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

Hepatic apolipoprotein B100 (apoB100) associates with lipids to form dense lipoprotein particles in the endoplasmic reticulum (ER) and is further lipidated to very low density lipoproteins (VLDL). Because the VLDL diameter can exceed 200 nm, classical ER-derived vesicles may be unable to accommodate VLDLs. Using hepatic membranes and cytosol to reconstitute ER budding, apoB100-containing vesicles sedimented distinct from those harboring more typical cargo but contained Sec23. Moreover, ER exit of apoB was inhibited by dominant-negative Sar1. Budding required Sar1 regardless of whether oleic acid (OA) was added to stimulate apoB lipidation; therefore, either large apoB100-lipoproteins reside in secretory vesicles, or full lipidation occurs post-ER. Using membranes from cells incubated in the presence or absence of OA, we determined that apoB100-lipoproteins in ER vesicles had not become lipidated to VLDLs. VLDL particles resided in the Golgi, but not the ER, after fractionation of OA-treated cells. We conclude that apoB100-lipoproteins exit the ER in COPII vesicles, but under conditions favorable for VLDL formation final lipid loading occurs post-ER.

Received for publication, June 27, 2003 , and in revised form, September 2, 2003.

^* This work was supported in part 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.

^¶ To whom correspondence should be addressed: Dept. of Medicine and Biochemistry, Box 1269, Mount Sinai School of Medicine, 1 Gustave Levy Place, New York, NY 10029. Tel.: 212-241-7152; Fax: 212-828-4178; E-mail: edward.fisher{at}mssm.edu.

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