Diacylglycerol O-acyltransferase 1 and 2 (DGAT1/2)

Diacylglycerol O-acyltransferase 1 (DGAT1) and 2 (DGAT2) are integral membrane enzymes that catalyze the final, rate-limiting step of triacylglycerol (TG) synthesis by esterifying diacylglycerol with a fatty acyl-CoA (UniProt, 2024). Although they catalyze the same reaction, they belong to distinct gene families—MBOAT for DGAT1 and DGAT2 for DGAT2—and exhibit different physiological roles and tissue distributions (PubMed, 2019). DGAT1 is highly expressed in the small intestine, where it is essential for dietary fat absorption and chylomicron assembly, while DGAT2 is the primary isoform in the liver and adipose tissue, regulating de novo lipogenesis and VLDL secretion (NIH, 2023). These enzymes are key therapeutic targets for metabolic diseases, including obesity, type 2 diabetes, and non-alcoholic steatohepatitis (NASH), as their inhibition reduces systemic and hepatic triglyceride levels (PubMed, 2023). Clinical development of DGAT1 inhibitors like pradigastat has been hampered by gastrointestinal side effects such as diarrhea and nausea, whereas DGAT2 inhibitors like ervogastat have shown better tolerability and significant efficacy in reducing liver fat (ClinicalTrials.gov, 2024). Recent research also suggests a role for these enzymes in cancer progression by modulating lipid droplet formation and cellular energy homeostasis (PubMed, 2024).

Other names

DGAT1DGAT2Acyl-CoA:diacylglycerol acyltransferase 1Acyl-CoA:diacylglycerol acyltransferase 2Diglyceride acyltransferaseARGP1DIAR7

Inhibition of the final, rate-limiting step of triacylglycerol synthesis by blocking the esterification of diacylglycerol with a fatty acyl-CoA.