Multiple functions of microsomal triglyceride transfer protein

Abstract

Microsomal triglyceride transfer protein (MTP) was first identified as a major cellular protein capable of transferring neutral lipids between membrane vesicles. Its role as an essential chaperone for the biosynthesis of apolipoprotein B (apoB)-containing triglyceride-rich lipoproteins was established after the realization that abetalipoproteinemia patients carry mutations in the MTTP gene resulting in the loss of its lipid transfer activity. Now it is known that it also plays a role in the biosynthesis of CD1, glycolipid presenting molecules, as well as in the regulation of cholesterol ester biosynthesis. In this review, we will provide a historical perspective about the identification, purification and characterization of MTP, describe methods used to measure its lipid transfer activity, and discuss tissue expression and function. Finally, we will review the role MTP plays in the assembly of apoB-lipoprotein, the regulation of cholesterol ester synthesis, biosynthesis of CD1 proteins and propagation of hepatitis C virus. We will also provide a brief overview about the clinical potentials of MTP inhibition.

Figure 1

Role of MTP in cellular cholesterol ester biosynthesis. (A) ACAT, a membrane integral enzyme is shown (yellow arrows) to convert free cholesterol present in the endoplasmic reticulum (ER) leaflets into cholesterol esters that remain within the membrane bilayer. MTP is shown to transfer both free cholesterol and cholesterol esters from the ER membranes to apoB-lipoproteins in the ER lumen. It should be pointed out that MTP could transfer both free and esterified cholesterol to apoB that is still associated with membranes. The thickness of orange arrows is meant to show that MTP most likely prefers cholesteryl esters over free cholesterol for transfer. (B) In MTP deficient conditions, transfer of free and esterified cholesterol to apoB-lipoproteins is reduced. Initially this might lead to accumulation of cholesteryl esters. When a high enough concentration of cholesteryl esters is achieved then ACAT activity is inhibited due to product inhibition leading to accumulation of free cholesterol. (C) In the absence of ACAT activity, it is anticipated that cells accumulate more free cholesterol. Indeed, this is known to happen in cells that do not secrete apoB-lipoproteins, such as macrophages. However, in cells that are able to synthesize apoB-containing lipoproteins, MTP can transfer free cholesterol to lipoproteins avoiding excess free cholesterol accumulation in the ER membrane.

Figure 2

Role of MTP in the biosynthesis of CD1 proteins: MTP transfers endogenous lipids to newly synthesized CD1 proteins in the ER (a). CD1 proteins also associate with β2-microglobulin (β2 m) before entering the secretory pathway (b). In the absence of MTP, group 1 CD1 proteins are subjected to proteasomal degradation (c). Group 2 CD1 proteins, on the other hand, are still transported to the plasma membrane in the absence of MTP. From the plasma membrane, CD1 proteins are constitutively internalized via clathrin-mediated endocytosis (d) and reach endosomal recycling compartment. In this compartment, saposins remove endogenous lipids and load different lipid antigens onto CD1 proteins (e). CD1 molecules with foreign lipids are recycled back to the plasma membrane (f), where they present their lipid antigens to restricted population of T cells.