Lipid transfer proteins in the assembly of apoB-containing lipoproteins

Abstract

Running Title: Lipid transfer proteins and lipoprotein assemblyAbbreviations used: ARF1, ADP ribosylation factor 1; AUP1, ancient ubiquitous protein 1; Blps, apoB-containing lipoproteins; CIDEB, cell death-inducing DFF45-like effector B; COPII, coat protein complex II; cLDs, cytoplasmic lipid droplets; ER, endoplasmic reticulum; MTTP, microsomal triglyceride transfer protein; PLTP, phospholipid transfer protein AbstractA better understanding of intracellular lipoprotein assembly may help identify proteins with important roles in lipid disorders. ApoB-containing lipoproteins 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 and is dependent on lipid re-synthesis in the endoplasmic reticulum and on a chaperone, namely microsomal triglyceride transfer protein. Precursors for lipid synthesis are obtained from extracellular sources and from cytoplasmic lipid droplets. Microsomal triglyceride transfer protein 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 apoB-containing lipoproteins 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. IntroductionHydrophobic lipids serve as a source of energy, structural components for membranes, and precursors of hormones. Owing to their hydrophobicity, lipids require special means of transport in the aqueous milieu of the human body. Three different modes of lipid transport are known. First, micellar solubilization of lipids in the intestinal lumen facilitates hydrolysis of dietary lipids in the lumen and uptake by enterocytes. Second, transport of lipids bound to proteins, e.g., albumin, occurs in the circulation. Third, the most efficient process of transporting lipids in bulk through an aqueous milieu of the blood circulation is via special protein-lipid macromolecular micelles called lipoproteins, which consist of a hydrophilic surface and a hydrophobic core. The hydrophilic surface is a monolayer of phospholipids that also contains free cholesterol and other exchangeable proteins called apolipoproteins. The lipoprotein core is devoid of proteins and consists of hydrophobic lipids, such as triacylglycerols, cholesteryl esters, vitamin E, and vitamin A. A major protein constituent of these lipoproteins is apoB, which is a very hydrophobic scaffolding protein. The apoB-containing lipoproteins (B-lps) are large spherical particles and are classif...

Plasma lecithin:cholesterol acyltransferase and phospholipid transfer protein activity independently associate with nonalcoholic fatty liver disease

“…These independent associations of LCAT and PLTP activity with an elevated FLI finding agree with the hypothesis that hepatic fat accumulation may enhance further increments in circulating LCAT and PLTP activities resulting from dysglycaemia and central obesity. On the other hand, animal experiments would suggest a pathogenic role for intracellular LCAT and PLTP as such in modulating NAFLD development . Mice studies have revealed that LCAT may aggravate hepatocellular endoplasmatic reticulum stress, although genetic LCAT deficiency could enhance triglyceride accumulation in the liver .…”

“…On the other hand, animal experiments would suggest a pathogenic role for intracellular LCAT and PLTP as such in modulating NAFLD development . Mice studies have revealed that LCAT may aggravate hepatocellular endoplasmatic reticulum stress, although genetic LCAT deficiency could enhance triglyceride accumulation in the liver . PLTP deficiency results in attenuated hepatic triglyceride accumulation in mice and may impair apoB secretion from hepatocytes by increasing intracellular oxidant status …”

“…Among various other factors, plasma lecithin:cholesterol acyltransferase (LCAT; EC 2.3.1.43) and phospholipid transfer protein (PLTP) play key roles in plasma lipoprotein metabolism and hepatic triglyceride handling. [17][18][19][20][21][22][23][24][25][26] LCAT is responsible for the esterification of free cholesterol to cholesteryl esters in high-density lipoproteins (HDL), thereby enabling the formation of larger high-density lipoprotein (HDL) particles. 17,21 PLTP is able to transfer phospholipids between very low-density lipoprotein (VLDL) and HDL and to convert HDL to smaller and larger particles.…”

Mechanisms of Transport and Delivery of Vitamin A and Carotenoids to the Retinal Pigment Epithelium

“…The resulting retinyl esters are incorporated with other neutral lipid esters (i.e., triacylglycerols and cholesteryl esters) and intact carotenoids into chylomicrons . Chylomicron assembly also requires the synthesis of microsomal triglyceride transfer protein (MTTP) and apolipoprotein B (apoB) . In the circulation much of the chylomicron triacylglycerol is hydrolyzed by lipoprotein lipase in extrahepatic tissues resulting in the production of a “chylomicron remnant.” The liver rapidly takes up the chylomicron remnants, and there is evidence that the retinyl esters are rapidly hydrolyzed and reesterified by LRAT during this process …”

Lipid Transfer Proteins: Introduction to the Thematic Review Series

“…The triglycerides are either packaged into chylomicrons, a lipid rich lipoprotein containing the unique non-exchangeable apolipoprotein Apo B48, or are stored as lipid droplets that may later be mobilized for the assembly of chylomicrons. The non-covalent coupling of triglycerides with apo B48 occurs co-translationally to initiate the assembly of chylomicrons and is mediated by the lipid transfer protein, microsomal triglyceride transfer protein (MTTP), whose function has been reviewed by Hussain and Sirwi (1). A deficiency of MTTP results in abetalipoproteinemia, a disease associated with low plasma lipids and vitamin A deficiency.…”