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.

FOOTNOTES

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§

To whom correspondence should be addressed: Dept. of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, P. O. Box 4000, Princeton, NJ 08543-4000. Tel.: 609-252-6288; Fax: 609-252-6964.

()

The abbreviations used are: MTP, microsomal triglyceride transfer protein; CETP, cholesteryl ester transfer protein; TG, triglyceride; CE, cholesteryl ester; DG, diglyceride; MG, monoglyceride; PC, phosphatidylcholine; PA, phosphatidic acid; lyso-PC, lysophosphatidylcholine; PE, phosphatidylethanolamine; PS, phosphatidylserine; PI, phosphatidylinositol; ethyl-PC, R-(Z,Z)-2-[[[2,3-bis[1-oxo-9-octadecenyl-1-oxy] propoxy]ethoxyphosphinyl]oxy]-N,N,N-trimethylethanaminium trifluoromethanesulfonate; VLDL, very low density lipoproteins; ER, endoplasmic reticulum; SUV, small unilamellar vesicles; apoB, apolipoprotein B.

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