Dgat2, or diacylglycerol O-acyltransferase 2, catalyzes the final step of triglyceride (TG) synthesis. It is involved in lipid metabolism pathways and is of great biological importance as lipid metabolism is crucial for cell function and organismal homeostasis [1,2,3,4]. Genetic models, such as knockout (KO) mouse models, have been valuable in studying its function.

In mice, Dgat2 deletion lowers liver TGs [1]. Inhibition of Dgat2 in cell and animal studies has shown multiple effects. It suppresses SREBP-1 cleavage, reduces fatty acid synthesis, and lowers TG accumulation and secretion from the liver. This occurs as Dgat2 inhibition shunts diacylglycerol into phospholipid synthesis, increasing phosphatidylethanolamine (PE) levels in the endoplasmic reticulum (ER), which in turn inhibits SREBP-1 cleavage [1]. In HepG2 cells, Dgat2 knockdown (KD) leads to suppressed mitochondrial function, decreased lipid droplets, and upregulated cell proliferation. Analyzing the transcriptome of non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) patients reveals a negative correlation in the expression of DGAT2 and 73 other lipid-associated genes. HCC patients with lower DGAT2 expression have a lower survival rate. Dgat2 KD also downregulates estrogen-related receptor alpha (ESRRA) and increases its dimerization with corepressor prospero homeobox 1 (PROX1), suggesting Dgat2 sustains hepatic mitochondrial stability via suppressing the ESRRA-PROX1 transcriptional network [2].

In conclusion, Dgat2 is essential for triglyceride synthesis and plays a role in maintaining hepatic mitochondrial sustainability and lipid metabolism. Studies using Dgat2 KO mouse models and cell-based knockdown experiments have provided insights into its functions in fatty liver disease and hepatocellular carcinoma, highlighting its potential as a therapeutic target for these diseases [1,2].