The role of PNPLA3 in health and disease

The human patatin-like phospholipase domain-containing 3 (PNPLA3) gene encodes for a protein of 481 amino-acids. The variant rs738409 is a cytosine to guanine substitution, encoding for the isoleucine to methionine substitution at position 148 (I148M) of the protein. This variant is strongly associated with the entire spectrum of liver disease. Although this variant is one of the best characterized and deeply studied, the mechanism behind the PNPLA3 and the liver disease is still not well defined. Functionally, it has become clear that the PNPLA3 protein is an enzyme with lipase activity towards triglycerides and retinyl esters, and acyltransferase activity on phospholipids. The aim of this review is to collect the latest data, obtained by in vitro and in vivo experiments, on the functional aspects of the PNPLA3 protein. Defining the precise role of PNPLA3 in the liver lipid metabolism, in order to develop novel therapies for the treatment of liver disease, will be the key of future research.