[PNPLA3 gene I148M polymorphism induces hepatic fibrosis via cholesterol metabolic dysregulation in mice].

Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M polymorphism (SNP rsID: rs738409; PNPLA3-I148M), a key genetic susceptibility factor for metabolic-associated fatty liver disease (MAFLD), is closely associated with disease progression. However, its mechanism in liver fibrosis remains to be elucidated. This study aimed to investigate the effects of PNPLA3-I148M overexpression on cholesterol metabolism, mitochondrial function, and fibrosis in the liver. We constructed the mouse models specifically overexpressing either the wild-type PNPLA3 (PNPLA3-WT) or PNPLA3-I148M in the liver. Liver fibrosis was induced via a high cholesterol-methionine and choline deficient (HC-MCD) diet. Our results showed that compared with the PNPLA3-WT group, mice overexpressing PNPLA3-I148M exhibited significantly elevated levels of total cholesterol, triglycerides, and free cholesterol, increased lipid droplet accumulation, and exacerbated steatosis and fibrosis in the liver. Mechanism studies revealed that PNPLA3-I148M interfered with cholesterol esterification and efflux by suppressing the expression of acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) and ATP-binding cassette transporter G1 (ABCG1). This led to abnormal accumulation of free cholesterol in the liver, activated dynamin-related protein 1 (DRP1), and ultimately induced mitochondrial dysfunction and the expression of fibrosis-related genes. These findings provide important in vivo evidence and reveal a potential molecular mechanism by which PNPLA3-I148M promotes the development of liver fibrosis, laying the groundwork for developing precision therapeutic strategies targeting PNPLA3-I148M in MAFLD.