1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (PNPLA3)

The 1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (also known as adiponutrin) is a membrane-bound enzyme belonging to the patatin-like phospholipase domain-containing protein family, primarily expressed in hepatocytes, hepatic stellate cells, and adipocytes. It catalyzes coenzyme A-dependent acylation of 1-acyl-sn-glycerol 3-phosphate (lysophosphatidic acid) to phosphatidic acid, a key step in glycerolipid biosynthesis, while also exhibiting triacylglycerol lipase, acylglycerol transacylase, and retinyl ester hydrolase activities that contribute to lipid droplet dynamics and acyl-chain remodeling. PNPLA3 localizes to the cytoplasm and recruits to lipid droplets, with its activity nutritionally regulated—downregulated in fasting states to favor lipogenesis. The common I148M variant (rs738409) impairs hydrolase function, elevates transacylase activity, promotes lipid accumulation on droplets, and drives hepatic steatosis and fibrosis in non-alcoholic fatty liver disease (NAFLD). This variant is strongly associated with progressive liver diseases, coronary artery disease, and type 2 diabetes, highlighting PNPLA3's role in metabolic dysregulation. Despite its therapeutic potential as a genetic biomarker, no approved drugs directly target PNPLA3, though its loss-of-function effects underscore challenges in modulating lipid metabolism without exacerbating steatosis.

Other names

adiponutrinpatatin-like phospholipase domain-containing protein 3