Glycerol-3-phosphate acyltransferase (GPAT)

Glycerol-3-phosphate acyltransferase (GPAT) is a critical enzyme that catalyzes the initial and rate-limiting step in the de novo synthesis of triacylglycerols (TAG) and glycerophospholipids (UniProt Q9HCL2, Q86UL3). It facilitates the acylation of glycerol-3-phosphate with a long-chain fatty acyl-CoA to form lysophosphatidic acid (LPA). In mammals, four distinct isoforms (GPAT1, GPAT2, GPAT3, and GPAT4) have been identified, localized to either the mitochondria or the endoplasmic reticulum, each with unique tissue distribution and regulatory properties (PMID: 22560296). GPAT1, the primary mitochondrial isoform, is highly expressed in the liver and is significantly upregulated during lipogenesis, making it a focal point for metabolic research (PMID: 17646645). Dysregulation of GPAT activity is strongly linked to the development of hepatic steatosis, insulin resistance, and obesity due to the excessive accumulation of lipid intermediates. Consequently, GPAT is considered a promising therapeutic target for metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). Pharmacological inhibition of GPAT, using experimental compounds like FSG67, aims to reduce TAG storage and promote fatty acid oxidation, although achieving isoform specificity remains a significant challenge in drug development (PMID: 21730171).

Other names

sn-glycerol-3-phosphate acyltransferaseGlycerol-3-phosphate O-acyltransferaseGPAT1GPAT2GPAT3GPAT4

Inhibition of the enzyme prevents the conversion of glycerol-3-phosphate and long-chain acyl-CoA to lysophosphatidic acid, thereby reducing the synthesis of triacylglycerols and redirecting fatty acids toward beta-oxidation.