DOI: 10.5061/dryad.7d7wm386j
title: PEMT-mediated phospholipid imbalance promotes age-associated metabolic dysfunction-associated steatotic liver disease progression

description: 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.
description: # PEMT-mediated phospholipid imbalance promotes age-associated metabolic
 dysfunction-associated steatotic liver disease progression Dataset DOI:
 [10.5061/dryad.7d7wm386j](https://doi.org/10.5061/dryad.7d7wm386j) ##
 Description of the data and file structure This dataset contains
 quantitative lipidomics profiling data derived from liver tissues of
 C57BL/6J mice. The experimental objective was to investigate
 age-associated alterations in the hepatic lipidome and to elucidate the
 role of PEMT-mediated phospholipid imbalance in the progression of
 metabolic dysfunction-associated steatotic liver disease (MASLD). Liver
 samples were collected from two specific age groups: young mice (6 months
 old, denoted as 6M) and aged mice (24 months old, denoted as 24M). Total
 lipids were extracted from the liver tissues and analyzed using liquid
 chromatography-mass spectrometry (LC-MS). The provided data includes the
 identification and quantification (in nmol/g) of various lipid species,
 highlighting significant differences in lipid composition between young
 and aged livers. ### Files and variables #### File: scheme.tiff
 **Description:** Schematic representation of the proposed mechanism. This
 figure illustrates how PEMT-mediated phospholipid imbalance acts as a
 driver for the progression of age-associated metabolic
 dysfunction-associated steatotic liver disease (MASLD). It summarizes the
 key metabolic alterations and signaling pathways identified in the study,
 highlighting the difference between young and aged liver phenotypes. ####
 File: Lipidomics_data1121.xlsx **Description:**  ##### Variables * **NO:**
 Row index number. * **lipid name:** The specific identification of the
 lipid species. * **Ontology:** The chemical classification or category of
 the lipid. * **6M-M-[Number] (nmol/g):** Quantitative lipid concentration
 in liver tissue from 6-month-old male mice. Unit: nanomoles per gram
 (nmol/g). * **24M-M-[Number] (nmol/g):** Quantitative lipid concentration
 in liver tissue from 24-month-old male mice. Unit: nanomoles per gram
 (nmol/g). * **Specialized abbreviations**：**6M:** 6 months old (Age).
 **24M:** 24 months old (Age). **M:** Male (Sex). **nmol/g:** Nanomoles per
 gram (unit of measurement). No specialized code or scripts were used for
 the generation of this specific data file; the values are derived from
 LC-MS quantitative analysis.