Review
Progress towards understanding the role of microsomal triglyceride
transfer protein in apolipoprotein-B lipoprotein assembly
David A. Gordon *, Haris Jamil
Division of Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
Received 27 October 1999; received in revised form 14 January 2000 ; accepted 14 January 2000
Abstract
The microsomal triglyceride transfer protein (MTP) is necessary for the proper assembly of the apolipoprotein B
containing lipoproteins, very low density lipoprotein and chylomicrons. Recent research has significantly advanced our
understanding of the role of MTP in these pathways at the molecular and cellular level. Biochemical studies suggest that
initiation of lipidation of the nascent apolipoprotein B polypeptide may occur through a direct association with MTP. This
early lipidation may be required to allow the nascent polypeptide to fold properly and therefore avoid ubiquitination and
degradation. Concerning the addition of core neutral lipids in the later stages of lipoprotein assembly, cell culture studies
show that MTP lipid transfer activity is not required for this to occur for apolipoprotein B-100 containing lipoproteins.
Likewise, MTP does not appear to directly mediate addition of core neutral lipid to nascent apoB-48 particles. However, new
data indicate that MTP is required to produce triglyceride rich droplets in the smooth endoplasmic reticulum which may
supply the core lipids for conversion of nascent, dense apoB-48 particles to mature VLDL. In addition, assembly of dense
apolipoprotein B-48 containing lipoproteins has been observed in mouse liver in the absence of MTP. As a result of these new
data, an updated model for the role of MTP in lipoprotein assembly is proposed. ß 2000 Elsevier Science B.V. All rights
reserved.
Keywords: Microsomal triglyceride transfer protein; Apolipoprotein B ; Very low density lipoprotein ; Chylomicron
1. Introduction
The microsomal triglyceride transfer protein
(MTP) is a heterodimeric neutral lipid transfer pro-
tein found in the lumen of the endoplasmic reticulum
of apolipoprotein B (apoB) lipoprotein secreting
cells, predominantly hepatocytes and intestinal enter-
ocytes [1]. The smaller 55 kDa subunit has been iden-
ti¢ed as protein disul¢de isomerase (PDI [2]). How-
ever, the disul¢de isomerase activity is not required
for the complex to transfer lipid [3] and the hetero-
dimer does not possess disul¢de isomerase activity
[2]. The larger 97 kDa subunit is a unique polypep-
tide that is responsible for the in vitro binding and
transfer of lipids [4]. Although MTP is capable of
transferring all of the lipid classes found in apoB
lipoproteins (triglycerides, cholesteryl esters, free
cholesterol, and phospholipid), in vitro analyses
show that it strongly prefers triglycerides and choles-
teryl esters [5].
1388-1981 / 00 / $ ^ see front matter ß 2000 Elsevier Science B.V. All rights reserved.
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* Corresponding author. Department of Age Related Diseases,
Bristol-Myers Squibb, Co., PO Box 4000, Rt. 206 and Province-
line Rd. (for FEDEX shipments only), Princeton, NJ 08543,
USA. Fax: (609) 2526964; E-mail : gordond@bms.com
BBAMCB 55627 24-5-00
Biochimica et Biophysica Acta 1486 (2000) 72^83
www.elsevier.com/locate/bba