Recent progress in understanding protein and lipid factors affecting hepatic VLDL assembly and secretion

Abstract

Excess lipid induced metabolic disorders are one of the major existing challenges for the society. Among many different causes of lipid disorders, overproduction and compromised catabolism of triacylglycerol-rich very low density lipoproteins (VLDL) have become increasingly prevalent leading to hyperlipidemia worldwide. This review provides the latest understanding in different aspects of VLDL assembly process, including structure-function relationships within apoB, mutations in APOB causing hypobetalipoproteinemia, significance of modulating microsomal triglyceride-transfer protein activity in VLDL assembly, alterations of VLDL assembly by different fatty acid species, and hepatic proteins involved in vesicular trafficking, and cytosolic lipid droplet metabolism that contribute to VLDL assembly. The role of lipoprotein receptors and exchangeable apolipoproteins that promote or diminish VLDL assembly and secretion is discussed. New understanding on dysregulated insulin signaling as a consequence of excessive triacylglycerol-rich VLDL in the plasma is also presented. It is hoped that a comprehensive view of protein and lipid factors that contribute to molecular and cellular events associated with VLDL assembly and secretion will assist in the identification of pharmaceutical targets to reduce disease complications related to hyperlipidemia.

Figure 1

Model of the N-terminal of apoB and positions of FHBL mutations. A, schematic diagram of apoB-100, with predicted locations of βα1, β1, α2, β2, and α3 domains are shown on the top. B, positions of non-truncating FHBL mutations within the N-terminal 1,000 amino acids of apoB-100. Mutations associated with phenotype of hypobetalipoproteinemia (hypoβ) are shown on the top, whereas mutations associated with phenotype of both hypoβ and hepatic steatosis are shown below. C, proposed homologous model of the N-terminal ~930 amino acids of apoB. The β-barrel, α-helical, and β sheet (C-sheet and A-sheet) are highlighted in green, cyan, red, and blue, respectively. Locations of Ala³¹, Gly²⁷⁵, Leu³²⁴, Leu³⁴³, Arg⁴⁶³, and Gly⁹¹² within the modeled βα1 domain are shown as yellow spheres.

Figure 2

Protein and lipid factors affecting VLDL assembly and secretion. The apoB polypeptide initiates lipid recruitment during translation and translocation (1); this process may or may not require the activity of MTP. The nascent apoB-lipid particle acquires, in a step-wise fashion, additional TAG (2). The activity of MTP is required for partitioning of TAG into the lumen (3) or the membranes of ER microsomes for VLDL assembly (4). The lumenal TAG substrate, referred to as "lumenal lipid droplet", exists in association with non-apoB apolipoproteins such as apoC-III (5). In addition to that synthesized from the de novo pathway (catalyzed by GPAT, AGPAT, PAP-1, and DGAT), the TAG substrate utilized for VLDL assembly is also derived from esterification of fatty acyl chains originated from TGH-mediated hydrolysis of existing storage and lumenal TAG pools (6) or from phospholipid turnover catalyzed by iPLA2 (7). The resulting VLDL precursor exits the ER through coatomer-mediated budding/vesiculation events (8), and maturation of VLDL₁ is achieved through ER/Golgi trafficking (9). Proteins associated with cytosolic lipid droplets, such as CideB and ADRP (10), influence VLDL assembly through an unknown mechanism. Molecular species of fatty acids have a profound impact on VLDL production; oleic acid (18:1 n-9) promotes (11) whereas EPA (20:5 n-3) and DHA (22:6 n-3) attenuate (12) VLDL assembly/secretion. Misfolded apoB protein and aborted lipoprotein assembly intermediates are targeted for intracellular degradation (13). Two degradative pathways, namely the ubiquitin/proteasome pathway (14) and autophagy (15), may involve formation of "crescent" structures that contain apoB and are in close association with cytosolic lipid droplets. ADRP, adipocyte differentiation-related protein; AGPAT, acylglycerol-3-phosphate acyltransferase; CDP-C, CDP-choline; CDP-E, CDP-ethanolamine; CT, CTP:phosphocholine cytidylyltransferase; DAG, diacylglycerol; DGAT, acyl-CoA:diacylglycerol acyltransferase; ET, CTP:phosphoethanolamine cytidylyltransferase; G-3-P, glycerol-3-phosphate; GPAT, glycerol-3-phosphate acyltransferase; LPA, lysophosphatidate; LPC, lysophophatidylcholine; LPE, lysophosphatidylethanolamine; MTP, microsomal triglyceride-transfer protein; PAP-1, phosphatidate phosphatase-1; PC, phosphatidylcholine; P-cho, phosphocholine; PE, phosphatidylethanolamine; P-eth, phosphoethanolamine; TAG, triacylglycerol; VLDL, very low density lipoproteins.