Acetyl-CoA carboxylase and triglyceride synthesis machinery

Acetyl-CoA carboxylase (ACC) and the triglyceride synthesis machinery constitute the primary enzymatic pathway for de novo lipogenesis (DNL) and the storage of lipids in the liver and adipose tissue [1]. ACC exists as two isoforms: ACC1, located in the cytosol to provide malonyl-CoA for fatty acid synthesis, and ACC2, located on the mitochondrial membrane to regulate fatty acid oxidation [2]. The triglyceride synthesis machinery, specifically diacylglycerol O-acyltransferase (DGAT1 and DGAT2), catalyzes the final, rate-limiting step of triacylglycerol formation by esterifying diacylglycerol with a fatty acyl-CoA [3]. In metabolic disorders such as non-alcoholic steatohepatitis (NASH) and metabolic-associated steatotic liver disease (MASLD), this pathway is pathologically upregulated, leading to excessive hepatic fat accumulation, lipotoxicity, and subsequent inflammation and fibrosis [2, 4]. Pharmacological targeting of this machinery involves small molecule inhibitors designed to reduce hepatic steatosis and improve metabolic health. Recent therapeutic strategies often employ dual inhibition of ACC and DGAT2 to maximize the reduction of liver fat while mitigating the compensatory increase in circulating triglycerides typically observed with ACC monotherapy [3, 5].

Other names

De novo lipogenesis (DNL) pathwayHepatic lipogenic machineryFatty acid and triglyceride synthesis pathwayACC-DGAT axis

Inhibition of Acetyl-CoA carboxylase (ACC1 and ACC2) to reduce the production of malonyl-CoA, thereby decreasing de novo lipogenesis and increasing fatty acid oxidation, often combined with the inhibition of diacylglycerol O-acyltransferase (DGAT1 or DGAT2) to block the final step of triglyceride assembly [2, 3].