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  • DGAT is specifically responsible for


    DGAT2 is specifically responsible for endogenous synthesis of TAGs which are then packed into cytosolic LDs in the cytosol for storage and luminal apolipoprotein B (apoB)-containing LDs in the ER lumen destined for VLDL secretion [122,127]. DGAT2 can also synthesize TAG using exogenous FAs and support VLDL production independent of DGAT1 activity [112] through interactions with its pathway-interactors and its own MGAT activity. It has been reported that both DGAT1 and DGAT2 recognize MAG as a substrate in the synthesis of TAG in addition to DAG [119]. In addition, DGAT2 contributes to TAG synthesis for LD expansion. DGAT1 possesses both overt and latent DGAT activities and specifically incorporates pre-formed FAs into TAGs. The overt activity synthesizes cytosolic LD-TAGs on the cytosolic side of the ER membrane for FA oxidation, and the latent activity produces TAGs that are assembled into LDs on the luminal side of the ER membrane contributing to VLDL secretion. The luminal LDs formed by the latent activity of DGAT1 do not contain apoB protein, but are coated with liver phospholipid transfer protein (PLTP) [[127], [128], [129]]. These non-apoB luminal LDs fuse with the apoB-containing LDs and contribute to the further lipidation of the nascent apoB-containing LDs in the ER lumen for their maturation and secretion as VLDL [122,[127], [128], [129]]. PLTP is thought to drive the fusion [128,129]. Although the presence of fully lipidated VLDL in the ER has been reported, VLDL maturation might also occur through ER/Golgi trafficking [13]. An important role of DGAT1 is that it re-esterifies DAG and MAG that are hydrolysed from existing LDs. Re-esterification of DAG on the luminal side of the ER membrane necessitates the transfer of both DAG and acyl-CoA across the membrane, which is believed to play an essential role in the communication between the cytosolic and luminal pools of TAG and the stereospecific distribution of the fatty acyl moieties of TAG. Re-esterification of hydrolysed products, DAG and FAs, in a ‘futile’ GMX1778 by DGAT1 has been thought to be a mechanism for regulating the flux of net hydrolysis, and to protect adipocytes from ER stress during lipolysis [130]. The ability of DAG to permeate biological membranes is well established [131], but acyl-CoA esters are impermeable to lipid bilayers and need a mechanism to be transported across the ER membrane for the re-synthesis of TAG on the luminal aspect of the ER. It is considered that the acyl carnitine carrier system, typically described in the mitochondrial inner membrane, may serve this function [132]. It should be noted that distinct from the liver and small intestine that secrete TAG as lipoproteins facilitated by apoB proteins [13,127,133], adipose tissue does not secrete lipoproteins due to the lack of apoB proteins but forms large LDs for storage of TAG instead. In rat liver, a minimum of 60% of the TAG incorporated into VLDL originates from stored hepatic TAG rather than direct transfer of de novo synthesized TAG on the cytoplasmic side of the ER membrane [5]. This stored hepatic TAG includes exogenous TAG from chylomicron remnants derived from the diet, and recycled endogenous TAG from VLDL remnants (Fig. 1). The recycled TAG is then hydrolyzed to DAG that is re-esterified to VLDL-TAG with a different stereospecific distribution of the fatty acyl moieties via the re-esterification of partial glycerides, DAG and MAG [12,133,134] (Fig. 1). Although an increase in cytoplasmic TAG does not always translate into an increased VLDL secretion [135], the overall rate of hepatic TAG lipolysis is positively correlated with VLDL-TAG output [136]. This turnover of TAG may also include degradation of TAG to MAG and re-esterification of MAG via the DGAT activity or the MAG pathway with addition of newly synthesized FA to the ‘old’ TAG backbone [137]. The type of FA incorporated after lipolysis is subject to the relative availability of individual FAs from the diet or in the plasma and their flux through the de novo synthesis pathways [138,139]. Although the flux can vary depending on the hormonal and nutritional milieu, a high carbohydrate intake that favours de novo lipogenesis can stimulate the synthesis of TAG containing new FA and glycerol [137]. In the fasting state, 26% of hepatic TAG and 23% of VLDL-TAG had endogenous FA synthesized from 2-carbon precursors derived from glucose, fructose, and amino acids [140].