Diacylglycerol O-acyltransferase 1 (DGAT1) (DGAT1)

Diacylglycerol O-acyltransferase 1 (DGAT1) is a vital metabolic enzyme located within the endoplasmic reticulum that plays a central role in lipid homeostasis by catalyzing the final step of triacylglycerol synthesis. Using diacylglycerol and fatty acyl-CoA as substrates, DGAT1 is responsible for the formation of triglycerides for storage in adipose tissue and for the assembly of lipoproteins in the liver and small intestine [1, 14]. In humans, it is highly expressed in the intestinal mucosa, where it is essential for dietary fat absorption and the subsequent secretion of chylomicrons [2, 16]. Because of its involvement in fat metabolism, DGAT1 has been identified as a significant therapeutic target for treating obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) [3, 21]. While several small-molecule inhibitors have demonstrated the ability to lower postprandial triglyceride levels and improve insulin sensitivity in clinical trials, their utility is frequently limited by mechanism-based gastrointestinal toxicity [12, 13]. Specifically, the inhibition of DGAT1 can lead to the accumulation of lipid intermediates in the gut, causing severe diarrhea and nausea, which mirrors the clinical phenotype of rare congenital DGAT1 deficiency [5, 17].

Other names

Diacylglycerol acyltransferase-1Acyl-CoA:diacylglycerol acyltransferase 1Diglyceride acyltransferaseARATARGP1DGATDIAR7ACATNAcyl-CoA retinol O-fatty-acyltransferaseAcyl-CoA:diacylglycerol acyltransferase-1

Inhibition of the enzyme-catalyzed esterification of diacylglycerol with fatty acyl-CoA, which prevents the final and committed step of triacylglycerol synthesis and reduces lipid absorption and accumulation.