PNPLA3, also known as patatin-like phospholipase domain-containing 3, encodes a 481-amino-acid protein with lipase activity towards triglycerides and retinyl esters, and acyltransferase activity on phospholipids. It is involved in hepatic lipid metabolism, with its function potentially balancing hepatic triglyceride storage and secretion [9]. The gene is of great significance as its variants are strongly associated with a spectrum of liver diseases, especially non-alcoholic fatty liver disease (NAFLD) [1,2,4,5,6,8].

In genetic studies, liver-specific knockout or acute knockdown of PNPLA3 in mice under lipogenic conditions led to aggravated liver steatosis and reduced plasma VLDL-triglyceride levels. This indicates that wild-type PNPLA3 facilitates the balance between hepatic triglyceride storage and secretion, and the I148M variant, a common genetic variation, may contribute to fatty liver disease development through a loss-of-function mechanism [7]. Also, in HepG2 cells, the PNPLA3 I148M mutation was shown to be involved in NF-κB-related inflammation regulation in NAFLD [3].

In conclusion, PNPLA3 is crucial in hepatic lipid metabolism and inflammation regulation. Mouse models with PNPLA3 knockout or knockdown have revealed its role in fatty liver disease, highlighting its potential as a therapeutic target for NAFLD and other related liver diseases [1,7].