Lipid transfer proteins in the assembly of apoB-containing lipoproteins

Abstract

A better understanding of intracellular lipoprotein assembly may help identify proteins with important roles in lipid disorders. apoB-containing lipoproteins (B-lps) are macromolecular lipid and protein micelles that act as specialized transport vehicles for hydrophobic lipids. They are assembled predominantly in enterocytes and hepatocytes to transport dietary and endogenous fat, respectively, to different tissues. Assembly occurs in the endoplasmic reticulum (ER) and is dependent on lipid resynthesis in the ER and on a chaperone, namely, microsomal triglyceride transfer protein (MTTP). Precursors for lipid synthesis are obtained from extracellular sources and from cytoplasmic lipid droplets. MTTP is the major and essential lipid transfer protein that transfers phospholipids and triacylglycerols to nascent apoB for the assembly of lipoproteins. Assembly is aided by cell death-inducing DFF45-like effector B and by phospholipid transfer protein, which may facilitate additional deposition of triacylglycerols and phospholipids, respectively, to apoB. Here, we summarize the current understanding of the different steps in the assembly of B-lps and discuss the role of lipid transfer proteins in these steps to help identify new clinical targets for lipid-associated disorders, such as heart disease.

Keywords: MTP; apolipoprotein B.

Fig. 1.

Schematic illustration of the role of lipid transfer proteins in the assembly of apoB-containing lipoproteins. apoB undergoes cotranslational lipidation during translocation through the ER membrane. Nascent apoB peptide interacts with the inner phospholipid monolayer, resulting in the formation of nucleation sites for the assembly of lipoproteins. MTTP is a critical chaperone for lipoprotein assembly and most likely helps by transferring lipids to nascent apoB and by physically interacting with apoB. PLTP is another ER lumenal lipid transfer protein that may assist the assembly of lipoproteins. As opposed to MTTP and PLTP, CIDEB and AUP1 are ER membrane proteins. CIDEB may facilitate addition of triacylglycerols to nascent apoB, whereas AUP1 appears to antagonize this function. Once a smaller primordial lipoprotein is formed, it undergoes a second step, namely, core expansion, which involves bulk addition of lipids from lumenal droplets to primordial lipoproteins, most likely involving membrane fusion. Several exchangeable apolipoproteins may stabilize the surface of these larger lipoproteins and assist in their assembly. All of these steps and proteins are critical for lipoprotein assembly and secretion in both the intestine and liver, except for PLTP that may not be as critical for intestinal lipoprotein assembly. The role of AUP1 has not been addressed in the intestine.