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J. Biol. Chem., Vol. 282, Issue 37, 26981-26988, September 14, 2007

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Identification of a Novel Isoform of Microsomal Triglyceride Transfer Protein^*

Peter J. Mohler¹, Mei-Ying Zhu, Anna M. Blade^¶, Amy-Joan L. Ham^||, Gregory S. Shelness^¶, and Larry L. Swift²

From the Department of Internal Medicine, University of Iowa School of Medicine, Iowa City, Iowa 52242, ^¶Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1040, and the Departments of ^||Biochemistry and Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2561

Microsomal triglyceride transfer protein (MTP) has been studied extensively, primarily because of its role in the assembly of very low density lipoproteins by the liver and chylomicrons by the intestine. Recent studies have suggested that MTP may also play key roles in other cellular processes. In this paper we report the identification of a novel splice variant of MTP in mice. This isoform, MTP-B, has a unique first exon located 2.7 kilobases upstream of canonical MTP (MTP-A) exon 1. The alternative exon encodes 35 amino acids compared with 20 amino acids encoded by exon 1 of MTP-A. MTP-B represents 90% of total MTP mRNA in mouse adipocytes and 3T3-L1 cells and <5% in mouse liver and intestine. Expression of the alternate isoform in mouse liver was confirmed by mass spectrometry. Co-transfection of COS cells with truncated forms of apoB and either MTP-A or MTP-B demonstrated that both isoforms are effective in the assembly and secretion of nascent apoB-containing lipoproteins. Confocal microscopy of 3T3-L1 cells transfected with enhanced green fluorescent protein or DsRed fusions of the two proteins revealed that MTP-A is localized to the endoplasmic reticulum, whereas MTP-B localizes primarily to the Golgi complex in these cells. We conclude that MTP-B functions similarly to MTP-A in lipoprotein assembly. However, in nonlipoprotein-secreting cells, such as the adipocyte, MTP-B may have different localization properties, perhaps reflecting a distinct role in lipid storage and mobilization.

Received for publication, January 18, 2007 , and in revised form, June 21, 2007.

^* This work was supported in part by National Institutes of Health Grants HL57984 (to L. L. S.) 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 Recipient of a National Scientist Development Grant from the American Heart Association.

² To whom correspondence should be addressed: CC-3327 Medical Center North, Department of Pathology, Vanderbilt University School of Medicine, 1161 21st Ave. South, Nashville, TN 37232-2561. Tel.: 615-343-2646; Fax: 615-343-7023; E-mail: larry.swift{at}vanderbilt.edu.

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