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J. Biol. Chem., Vol. 281, Issue 16, 11019-11027, April 21, 2006

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Phospholipid Transfer Activity of Microsomal Triacylglycerol Transfer Protein Is Sufficient for the Assembly and Secretion of Apolipoprotein B Lipoproteins^*

Paul Rava, George K. Ojakian, Gregory S. Shelness, and M. Mahmood Hussain^¶1

From the Departments of Anatomy and Cell Biology and ^¶Pediatrics, SUNY Downstate Medical Center, Brooklyn, New York 11203 and the Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157

Human microsomal triacylglycerol transfer protein (hMTP) is essential for apolipoprotein B (apoB)-lipoprotein assembly and secretion and is known to transfer triacylglycerols, cholesterol esters, and phospholipids. To understand the relative importance of each lipid transfer activity, we compared the ability of hMTP and its Drosophila ortholog (dMTP) to assemble apoB lipoproteins and to transfer various lipids. apoB48 secretion was induced when co-expressed with either hMTP or dMTP in COS cells, and oleic acid supplementation further augmented secretion without altering particle density. C-terminal epitope-tagged dMTP (dMTP-FLAG) facilitated the secretion of apoB polypeptides in the range of apoB48 to apoB72 but was 50% as efficient as hMTP-FLAG. Comparison of lipid transfer activities revealed that although phospholipid transfer was similar in both orthologs, dMTP was unable to transfer neutral lipids. We conclude that the phospholipid transfer activity of MTP is sufficient for the assembly and secretion of primordial apoB lipoproteins and may represent its earliest function evolved for the mobilization of lipid in invertebrates. Identification of MTP inhibitors, which selectively affect transfer of a specific lipid class, may have therapeutic potential.

Received for publication, November 30, 2005 , and in revised form, February 6, 2006.

^* This work was supported in part by National Institutes of Health Grants DK46900 and HL64272 (to M. M. H.) and HL49373 (to G. S. S.). 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. Fax: 718-270-2462; E-mail: Mahmood.Hussain{at}downstate.edu.

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