PNPLA3 Gene: Function, I148M Variant, and Liver Disease Risk

The PNPLA3 gene encodes a protein called adiponutrin, which belongs to the patatin-like phospholipase family. It is primarily expressed in the liver and adipose tissue, where it localizes to lipid droplets and exhibits both lipase and acyltransferase activities. PNPLA3 plays a critical role in lipid metabolism, particularly in the hydrolysis of triglycerides and the remodeling of lipid droplets. A common missense variant, I148M (rs738409), is strongly associated with increased susceptibility to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and liver fibrosis. This variant impairs the enzymatic activity of PNPLA3, leading to lipid accumulation in hepatocytes and altered hepatic lipid homeostasis.

Tissue Expression

Cell Line Expression

Hotspot Mutations

Mutation functional classification

• Triglyceride metabolism

• Lipid droplet formation and degradation

• Fatty acid beta-oxidation (indirectly)

PNPLA3 (adiponutrin) is a 481-amino acid protein with a patatin-like domain at the N-terminus, which contains the catalytic serine-aspartate dyad. It is anchored to lipid droplets via a hydrophobic region. The protein exhibits both triacylglycerol lipase and acylglycerol transacetylase activities, playing a dual role in lipid metabolism. The I148M variant, located in the patatin domain, disrupts the catalytic site, reducing lipase activity and leading to lipid accumulation. PNPLA3 is predominantly expressed in the liver and adipose tissue, and its expression is regulated by nutritional status (upregulated by feeding and insulin).