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.