Integrated Liver and Brain Lipidomics Reveals Coordinated Remodeling in a High-Fat Diet Plus Binge Ethanol Mouse Model of Alcohol-Associated Liver Disease

Abstract

Alcohol-associated liver disease (ALD) has imposed a substantial public health burden in the United States, and alcohol consumption induces systemic lipid dysregulation in ALD. To investigate this, the lipidomes of liver and brain tissues from long-term high fat diet (HFD) feeding and HFD with single ethanol (EtOH) binge (HFD + EtOH) mice were characterized by comprehensive two-dimensional (2D) liquid chromatography–mass spectrometry. Multiple database matching was used for high-confidence lipid identification. Univariable and multivariable analyses were employed to identify lipids with significantly altered abundance between HFD + EtOH and HFD mice. Furthermore, differential correlation analysis and cross-tissue codysregulation mapping were performed. Our data indicated that alcohol feeding induced profound tissue-specific lipidomic alterations. Triglycerides increased significantly, and phospholipids decreased in the livers of alcohol-treated mice, whereas their brains exhibited elevation of oxidized lipids with subclass-divergent changes in glycerolipids, glycerophospholipids, and sphingolipids. Differential correlation analysis revealed extensive remodeling of lipid interaction networks in the alcohol-exposed brain. Cross-tissue analysis identified 18 codysregulated lipids demonstrating a strongly correlated lipid regulation shift in HFD + EtOH mice. Collectively, alcohol rewires organ-specific lipidomes through distinct mechanisms and induces correlated multitissue lipid dysregulation, suggesting potential lipid-centric communication along the liver-brain axis. These findings provide novel insights into ALD pathogenesis and reveal potential biomarkers for multiorgan involvement.