Deletion of phosphatidylethanolamine methyltransferase promotes the spontaneous development of hepatic steatosis, inflammation, and fibrosis in young mice.

Abstract

Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes the transfer of methyl groups to phosphatidylethanolamine to generate phosphatidylcholine (PC). PC produced de novo through this pathway is preferentially used for very-low-density lipoprotein assembly and is essential for its normal hepatic secretion as well as for bile acid detoxification. While human PEMT loss-of-function polymorphisms are linked to increased metabolic dysfunction-associated steatotic liver disease risk, the enzyme's role as a primary driver of progressive liver disease remains underexplored. We utilized PEMT knockout (PEMT KO) mice on a standard chow diet to model this deficiency. Histopathological analysis showed that while 2-month-old PEMT KO mice were protected, 6-month-old KOs of both sexes spontaneously developed extensive micro- and macrovesicular steatosis, parenchymal inflammation, and granulomatous inclusions. This severe, age-dependent pathology was confirmed by elevated hepatic triglyceride levels, bile acids, impaired methylation potential, and a cascade of secondary injuries, including increased oxidative stress, impaired proteasomal function, and the induction of cellular senescence markers. This bile acid toxicity and oxidative stress activated the central innate immune sensor, the NLRP3 inflammasome, driving pronounced macrophage infiltration and chronic inflammation. Picrosirius red staining and protein analysis confirmed the progression to severe pericellular fibrosis. Our study establishes that PEMT deficiency is sufficient to initiate and drive the complete progression from steatosis to advanced liver fibrosis, identifying PEMT as a critical metabolic checkpoint and a potent therapeutic target for mitigating progressive liver disease.