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  • In contrast DGAT does not interact with mitochondria


    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 Complementing the localization studies, experiments with gene knockout mice and labelled substrates have provided further evidence of source-dependent preferential use of FA by the two DGAT isotypes. Liver-specific Dgat1 knockout mice are resistant to hepatic steatosis induced by high fat diet and prolonged fasting; both events are characterized by delivery of exogenous FA to the liver [112]. The exogenous FA could originate in the diet or in the adipose tissue and be transported into the evofosfamide sale via lipoprotein remnants and albumin (Fig. 1). However, DGAT1 inhibition does not protect against hepatic steatosis caused by lipodystrophy and liver X receptor activation, which together increase de novo lipogenesis in the liver [112]. Further investigations using HepG2 cells, a human hepatoma cell line, and radiolabelled substrates have confirmed that DGAT1 preferentially acylates exogenous FA, whereas DGAT2 uses de novo synthesized FA [113]. Homozygous Dgat2 deficient mice die soon after birth and do not contain fat deposits in liver or other tissues [114], suggesting that DGAT2 plays a fundamental role in fat synthesis in mammals. Wurie et al. [113] reported that inhibition of DGAT2 in HepG2 cells has a minor effect on the incorporation of exogenous 14C-oleate into TAG but is rate-limiting for the incorporation of both 3H-glycerol and endogenous FA derived from 14C-acetate, indicating DGAT2 predominantly uses endogenously synthesized FA as substrate. Choi et al. [115] have also shown marked reduction in hepatic TAG when rats fed on a high-fat hepatic steatosis-inducing diet were treated with antisense oligonucleotides to block Dgat2 expression. Blocking Dgat1 expression did not protect the rats against hepatic steatosis on a high-fat diet [115]. These findings seem to suggest that DGAT1 preferentially esterifies exogenous FA whereas DGAT2 has a specific role in incorporating de novo synthesized FA to form TAG. However, Li et al. [116] report that incorporation of FA formed from 3H-acetate into TAG synthesized by primary mouse hepatocytes is not affected by the inhibition of either DGAT1 or DGAT2 alone, and incorporation of 13H-oleate is only ‘slightly’ less in DGAT2-inhibited cells. Inhibition of both DGATs of the mouse hepatocytes on the other hand led to a ‘dramatic’ reduction in TAG synthesis, irrespective of whether FA was endogenously synthesized or supplied exogenously. This led Li et al. [116] to hypothesize that DGAT1 and DGAT2 can compensate for each other to synthesize TAG in mouse hepatocytes. This hypothesis correlates with the phenotype of Dgat1 knockout mice that these mice show normal fat absorption [112], possibly due to expression of DGAT2 in the small intestine [117] that can form TAG from dietary fat. However it is not congruent with the phenomenon of Dgat2 knockout mice that these mice die soon after birth and do not contain fat deposits in their liver or other tissues [114], indicating DGAT1 cannot efficiently esterify endogenously formed FAs. The latter disagreement could be due to the fact that the HepG2 cells incubations by Li et al. [116] were performed over prolonged time (4 h), during which the turnover of TAG might have been substantial and the differentiation between de novo and preformed FAs may have been lost due to rapid lipolysis/re-esterification. When HepG2 cells were incubated with 13C-D5-glycerol or 13C18-oleic acid and the TAG was measured acutely (0.5–2 h), selective DGAT1 and DGAT2 inhibitors demonstrated that 13C-D5-glycerol-incorporated TAG synthesis was mediated by DGAT2, not DGAT1. Conversely, 13C18-oleoyl-incorporated TG synthesis was predominantly mediated evofosfamide sale by DGAT1 [118]. Together, this evidence suggests that DGAT2 performs both functions in esterifying endogenous and exogenous FAs, whereas DGAT1 seems to esterify only pre-formed FAs to synthesize TAG.