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  • There is evidence that DGAT subunits


    There is evidence that DGAT2 subunits can interact with each other and are capable of forming a multimeric complex [82,105]. Besides, DGAT2 is part of a large protein complex involved in TAG synthesis [105]. A multi-subunit protein complex with TAG synthetic activity isolated from rat intestinal villus Carmoxirole hydrochloride was the earliest evidence for such a complex. This complex was reported to have acyl-CoA synthetase, acyl-CoA acyltransferase, MGAT, and DGAT activities [108] Within the ER membrane, DGAT2 is found in the vicinity of another enzyme, stearoyl-CoA desaturase 1 (SCD1). SCD1 catalyzes the synthesis of mono-unsaturated FAs from palmitate (C16:0) and stearate (C18:0) that are de novo synthesized or derived from the diet and adipose tissue [107] (Fig. 1). The proximity of MGAT2, FATP1, and SCD1 to DGAT2 may facilitate channelling of the necessary substrates (DAG and fatty acyl-CoA) to DGAT2 for robust TAG synthesis [[105], [106], [107]]. Disruption of the SCD1 gene leads to reduced levels of hepatic TAGs, a deficiency that cannot be corrected by dietary supplementation of mono-saturated FA [109]. This points to the possibility of different substrate pools of endogenous FAs and exogenous FAs that may be located in different microenvironments of the ER where they are utilized for different purposes. Owing to its specific localization in the ER, DGAT2 may associate with the pool of de novo FAs that is not available to DGAT1, which is localized elsewhere [108,109]. In contrast, DGAT1 does not interact with mitochondria and LDs but can form dimers and tetramers [76]. It has been reported that the hydrophilic N-terminal region of DGAT1, which is not required for acyltransferase activity, has the roles in regulating enzyme activity and the formation of dimers and tetramers [76]. Various lines of evidence have shown that acyl-CoAs bind to the N-terminal region of DGAT1 and modulate its enzyme activity with positive cooperativity as a function of acyl-CoA concentration, suggesting DGAT1 may be regulated through allosteric interaction [87,110,111]. This is consistent with the fact that DGAT1 self-associates to form a quaternary structure, and most allosteric enzymes exhibit quaternary structure.
    Source of fatty acids The preferences for source of FAs for DGAT1 and DGAT2 are related to their membrane topologies, subcellular locations, interactions with other proteins or organelles (discussed in the former section), and their differential expression, substrate specificities, and enzyme kinetics. According to UniProt protein database (, human DGAT1 is expressed at a high level in adrenal gland and small intestine, at a medium level in liver and pancreas, and at low level in heart muscle, Carmoxirole hydrochloride kidney, and skin, whereas human DGAT2 is expressed predominantly in liver and white adipose tissue, at a lower level in mammary gland and peripheral blood leukocytes, and is also expressed in sebaceous glands of normal skin but decreased ipsoriatic skin. In mouse, DGAT1 is expressed at a medium level in liver, kidney, and heart and at a low level in skeletal muscle tissue, whereas DGAT2 is expressed at a high level in liver, testis, brain, and lung. DGAT1 has broader substrate specificity synthesizing retinal esters, ether lipids, and waxes in addition to TAG [111], and with a higher K than DGAT2 [119], indicating DGAT1 requires a higher substrate concentration for apparent DGAT activity. It is reported that DGAT1 has an apparent Km of 13.9 μM for palmitoyl coenzyme A [120], whereas the Km for DGAT2 for oleoyl-CoA is 8.3 μM [54]. DGAT1 is subject to allosteric regulation with positive cooperativity in terms of acyl-CoA levels [110,111]. It has been shown that DGAT1 is more active at higher (>200 μM) oleoyl-CoA concentrations associated with an influx of exogenous FA in an in vivo system, whereas DGAT2 is more active at lower oleoyl-CoA concentrations (50 μM or less) [42]. This suggests that DGAT1 activity is proportionately increased over DGAT2 at high substrate concentrations, such as with exogenous addition of FA or with the high levels of lipolysis seen as a complication in metabolic syndrome and insulin resistance [42,45,108].