PEMT-mediated phospholipid imbalance promotes age-associated metabolic dysfunction-associated steatotic liver disease progression

Metabolically-dysfunction-associated steatotic liver disease [MASLD;
previously known as nonalcoholic fatty liver disease (NAFLD)] is a
prevalent chronic liver disorder strongly associated with aging, yet the
mechanisms underlying age-related hepatic lipid dysregulation remain
incompletely defined. This study investigates how aging alters hepatic
phospholipid metabolism and the contribution of phosphatidylethanolamine
N-methyltransferase (PEMT) to MASLD progression. Here, lipid accumulation
was characterized in the livers of 2-, 6-, 12-, 18-, and 24-month-old
mice, revealing age-dependent increases in hepatic triglyceride (TG),
total cholesterol (TC), and lipid droplet formation. Lipidomic analysis
revealed a marked imbalance in phospholipid composition, characterized by
increased phosphatidylcholine (PC) and decreased phosphatidylethanolamine
(PE), resulting in a 2.5-fold increase in the PC/PE ratio in 24-month-old
mice compared to 6-month-old controls. Mechanistically, PEMT, a key enzyme
regulating PC and PE metabolism, exhibited significantly increased
expression (~2.4-fold at the protein level) in aged livers, suggesting a
pivotal role in driving the observed phospholipid imbalance in vitro. PEMT
inhibition significantly attenuated lipid droplet accumulation by ~30% and
reduced intracellular TG levels by ~20% in D-galactose-induced senescent
AML12 hepatocytes under lipid stress, compared to non-silenced senescent
controls. These findings suggest that aging-driven PEMT
[JH1] overexpression promotes phospholipid remodeling and hepatic
lipid accumulation. By leveraging a natural aging mouse model, our study
provides the first evidence linking PEMT activity to age-associated
phospholipid dyshomeostasis, revealing a previously unknown mechanistic
axis distinct from diet-induced MASLD and offering new therapeutic
insights.