Enzymes of triglyceride synthesis

The enzymes of triglyceride synthesis comprise a group of enzymes responsible for the stepwise assembly of triacylglycerols (TAGs), the primary energy storage molecules in mammals [1, 8]. This metabolic process, known as the glycerol-3-phosphate or Kennedy pathway, involves sequential reactions catalyzed by glycerol-3-phosphate acyltransferase (GPAT), 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT), phosphatidate phosphatase (Lipin), and diacylglycerol O-acyltransferase (DGAT) [8, 13]. Additionally, the monoacylglycerol acyltransferase (MGAT) pathway provides an alternative route for TAG synthesis, particularly in the intestine [10]. DGAT, which exists as two distinct isoforms (DGAT1 and DGAT2), catalyzes the final and only committed step of TAG synthesis [1, 2]. These enzymes are primarily localized in the endoplasmic reticulum and are highly expressed in tissues active in lipid metabolism, such as the liver, adipose tissue, and small intestine [1, 7]. Dysregulation of triglyceride synthesis enzymes is a central feature of metabolic diseases, including obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) [1, 28]. Excessive TAG accumulation in non-adipose tissues (ectopic fat) leads to lipotoxicity and insulin resistance [2, 5]. Consequently, these enzymes, particularly the DGAT isoforms, have become prominent therapeutic targets [2, 9]. Pharmacological inhibitors of DGAT1 and DGAT2 are being developed to lower systemic and hepatic triglyceride levels [7, 23]. While DGAT1 inhibitors have shown efficacy in reducing postprandial lipemia and body weight, their clinical development has been limited by gastrointestinal side effects [7, 10]. DGAT2 inhibitors, such as ervogastat, are currently being investigated for the treatment of NASH and have shown promise in reducing liver fat content [9, 23].

Other names

Triglyceride synthesis pathwayTriacylglycerol biosynthetic enzymesGlycerol-3-phosphate pathway enzymesKennedy pathway enzymesTriacylglycerol synthesis enzymes

Inhibition of diacylglycerol O-acyltransferase (DGAT1 or DGAT2), inhibition of glycerol-3-phosphate acyltransferase (GPAT), and reduction of triglyceride synthesis and secretion.