Pnpla3-flox Mouse

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 [8]. It is involved in hepatic lipid metabolism, playing a role in the balance between hepatic triglyceride storage and secretion [6]. The genetic variant rs738409, which leads to an isoleucine to methionine substitution at position 148 (I148M) of the protein, is strongly associated with non-alcoholic fatty liver disease (NAFLD) and other liver diseases [1,2,3,4,5,7,8].

In mice, liver-specific knockout or acute knockdown of Pnpla3 under lipogenic conditions leads to aggravated liver steatosis and reduced plasma very-low-density lipoprotein-triglyceride levels. Similarly, I148M-knockin mice show decreased hepatic triglyceride secretion during lipogenic stimulation. These findings suggest that wild-type Pnpla3 facilitates the balance between hepatic triglyceride storage and secretion, and the I148M variant's loss-of-function may contribute to fatty liver disease [6].

In conclusion, Pnpla3 is crucial for hepatic lipid metabolism, especially in maintaining the balance of triglyceride storage and secretion. Mouse models, such as gene knockout and knockin models, have provided valuable insights into the role of Pnpla3 in fatty liver disease, highlighting its potential as a therapeutic target for liver-related diseases [1,6].