Diacylglycerol acyltransferase 2 (DGAT2)

Class

Small-molecule DGAT2 inhibitor (ervogastat)

Pathway

Triglyceride synthesis — blocks the final step of hepatic triglyceride esterification, reducing lipotoxic diacylglycerol/triglyceride accumulation

Diacylglycerol acyltransferase 2 (DGAT2) is an enzyme embedded in the endoplasmic reticulum membrane of cells, most abundantly in the liver and fat tissue. It performs the final chemical step in triglyceride synthesis, attaching a fatty acid to a diacylglycerol (DAG) molecule to form triglyceride, the storage form of fat. In the liver, when fatty acid delivery exceeds the capacity for oxidation or export, triglyceride and its precursor DAG accumulate within hepatocytes (liver cells), a state called hepatic steatosis. Excess DAG in particular is considered 'lipotoxic,' interfering with insulin signaling and contributing to cellular stress that can progress to inflammation and fibrosis. Inhibiting DGAT2 is a strategy aimed at reducing the liver's overall capacity to synthesize new triglyceride, thereby lowering fat accumulation in hepatocytes. This mechanism is of broad interest in metabolic liver disease, where excess hepatic fat storage and its downstream inflammatory consequences are central disease drivers. DGAT2 is distinguished from a related enzyme, DGAT1, by its tissue distribution and its dominant role in hepatic and adipose triglyceride synthesis, making it a more liver-focused target for addressing fatty liver disease.