Abstract
Diacylglycerol acyltransferases (DGAT) 1 and 2 catalyse the final step in triacylglycerol (TAG) synthesis, the esterification of fatty acyl-CoA to diacylglycerol. Despite catalysing the same reaction and being present in the same cell types, they exhibit different functions on lipid metabolism in various tissues. Yet, their roles in skeletal muscle remain poorly defined. In this study, we investigated how selective inhibitors of DGAT1 and DGAT2 affected lipid metabolism in human primary skeletal muscle cells. The results showed that DGAT1 was dominant in human skeletal muscle cells utilizing fatty acids (FAs) derived from various sources, both exogenously supplied FA, de novo synthesised FA, or FA derived from lipolysis, to generate TAG, as well as being involved in de novo synthesis of TAG. On the other hand, DGAT2 seemed to be specialised for de novo synthesis of TAG from glycerol-3-posphate only. Interestingly, DGAT activities were also important for regulating FA oxidation, indicating a key role in balancing FAs between storage in TAG and efficient utilization through oxidation. Finally, we observed that inhibition of DGAT enzymes could potentially alter glucose–FA interactions in skeletal muscle. In summary, treatment with DGAT1 or DGAT2 specific inhibitors resulted in different responses on lipid metabolism in human myotubes, indicating that the two enzymes play distinct roles in TAG metabolism in skeletal muscle.
Highlights
Diacylglycerol acyltransferases (DGAT) 1 and 2 catalyse the final step in triacylglycerol (TAG) synthesis, the esterification of fatty acyl-CoA to diacylglycerol
DGAT1 and DGAT2 have recently been shown to have distinct and overlapping functions for TAG synthesis in adipocytes[17], where DGAT1 have been linked to the lipolysis-re-esterification cycle of preformed fatty acids (FAs), a process that may protect the endoplasmic reticulum from lipotoxic stress and adipose tissue inflammation[18]
Using highly specific small-molecule inhibitors of DGAT1 (A922500, D1i)[26] and DGAT2 (JNJ-DGAT2-A, D2i)[16] we investigated the effects of their specific inhibition on TAG synthesis in FA metabolism using labelled precursors
Summary
Diacylglycerol acyltransferases (DGAT) 1 and 2 catalyse the final step in triacylglycerol (TAG) synthesis, the esterification of fatty acyl-CoA to diacylglycerol. Upregulation of DGAT1 in mouse skeletal muscle increased TAG synthesis and protected against high-fat diet-induced insulin resistance[21], whereas overexpression of DGAT2 in glycolytic muscle resulted in an increased amount of TAG, ceramides and long-chain fatty acyl-CoAs, followed by an impaired insulin signalling[22]. Overall, these reports emphasize the potential for specialized roles of DGAT1 and DGAT2 in various tissues. We examined if inhibition of DGAT enzymes could influence glucose metabolism in human myotubes
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