Microsomal Triglyceride Transfer Protein

Abstract

Microsomal triglyceride transfer protein (MTP) is a lipid transfer protein that is required for the assembly and secretion of very low density lipoproteins by the liver and chylomicrons by the intestine. To further elucidate the nature of the lipid molecule binding and transport site on MTP, we have studied the relative rates at which MTP transports different lipid species. Assay conditions were chosen in which there were minimal changes in the physical properties of the substrate membranes so that transfer rates would reflect MTP-lipid interactions at a membrane surface. Lipid transport rates decreased in order of triglyceride > cholesteryl ester > diglyceride > cholesterol > phosphatidylcholine. Changes in the hydrophobic nature of a lipid molecule by the addition of a fatty acid, modulated the ability of MTP to transport it. Addition of one acyl chain from diglyceride to triglyceride, lysophosphatidylcholine to phosphatidylcholine, or cholesterol to cholesteryl ester increased the rate of MTP-mediated transport 10-fold. In contrast, the lipid transport rate was insensitive to the changes in the structure or charge of the polar head group on phospholipid substrates. Zwitterionic, net negative, or net positive charged phospholipid molecules were all transported at a comparable rate. The ability of MTP to transport lipids is strongly correlated to the binding of these lipids to MTP. Thus, MTP has a specific preference for binding and transporting nonpolar lipid compared with phospholipids, and within a class of lipid molecules, a decrease in polarity increases its tendency to be transported.

Hepatic microsomal triglyceride transfer protein messenger RNA concentrations are increased by dietary cholesterol in hamsters

“…50% of hamster VLDL chol is esterified (Salter, unpublished observations). It is entirely possible that MTP is involved in the transport of cholesteryl ester as well as triacylglycerol [23]. Interestingly, in the hamster, hepatic MTP mRNA concentrations tend to correlate better with lipoprotein cholesterol than with triacylglycerol concentrations ( [5,6] and this work).…”

“…It is possible that increased amounts of MTP are required to transfer the increased amount of lipid to the maturing lipoprotein particle. Functional MTP appears to be required for VLDL production [2], facilitating both translocation of apoB across the endoplasmic reticulum and its association with lipid [14][15][16] and MTP appears to be rate limiting for these processes in cultured cells [17,18]. However, reduced VLDL output in vivo does not appear to be associated with reduced MTP activity [7].…”

Role of insulin in hepatic fatty acid partitioning: emerging concepts

“…Assembly of TAG-rich apoB lipoproteins has an obligatory requirement for a lumenal microsomal triacylglycerol transfer protein [109]. It catalyses the transfer of TAG and other nonpolar lipids between membranes and liposomes in itro [110] and its function in i o may be to facilitate the transfer of TAG across the ER membrane and into the nascent apoB polypeptide. It is noteworthy that this lumenal protein occurs as a heterodimer in association with protein disulphide-isomerase (which is essential for the correct folding of secretory proteins involving disulphide bridges) in the lumen of the ER [110].…”

“…It catalyses the transfer of TAG and other nonpolar lipids between membranes and liposomes in itro [110] and its function in i o may be to facilitate the transfer of TAG across the ER membrane and into the nascent apoB polypeptide. It is noteworthy that this lumenal protein occurs as a heterodimer in association with protein disulphide-isomerase (which is essential for the correct folding of secretory proteins involving disulphide bridges) in the lumen of the ER [110]. Its apparently obligatory involvement in VLDL assembly and secretion may reflect a putative dual function in the correct folding of apoB and the concomitant transfer of TAG to the nascent VLDL particle.…”

Transmembrane Lipid Transfer Is Crucial for Providing Neutral Lipids during Very Low Density Lipoprotein Assembly in Endoplasmic Reticulum

“…MTP locates in the luminal space of ER by forming heterodimers with protein disulfide isomerase (6). MTP binds various lipid molecules, including TG and then presents those lipids to apoB (7). It was clearly shown that newly synthesized apoB in cells lacking MTP failed to associate with lipids and subsequently the apoB was degraded (8).…”