ABSTRACT: MASH is a metabolic disorder disease initially driven by imbalance between lipid acquisition and lipid disposal, yet the hepatic lipidomic landscape that underpins this imbalance remains incompletely defined. Increasing studies indicated that special lipotoxic species play an important role in the development and progression of MASH. Currently, evidence regarding the lipid classes associated with MASH pathogenesis is still limited and inconsistent. Our study utilized non-targeted lipidomic analysis to systematically analyze the hepatic lipid alterations in HFHC diet-induced early-stage MASH mice and MCD diet-induced advanced stage MASH mice. A total of 15 lipid classes were detected in both MASH models, including TAGs, DAGs, PCs, PEs, Cers, SMs, PIs, PSs, LPCs, PGs, PAs, DLCLs, LPEs, LPIs, and LPSs. Among these, hepatic TAGs, PCs, PEs, Cers, and SMs were highly abundant in HFHC diet-induced MASH mice, whereas hepatic TAGs, PCs, SMs, DAGs, and Cers were highly abundant in MCD diet-induced MASH mice. Notably, the majority of TAGs, DAGs, and Cers were significantly increased, while most PEs were significantly decreased in both models. In contrast, most PCs were significantly decreased in HFHC diet-induced MASH mice but displayed bidirectional changes in MCD diet-induced MASH mice, and SMs exhibited bidirectional changes in both models. Collectively, these findings reveal both shared and model-specific features of hepatic lipid remodeling in MASH, and provide important scientific evidence to guide the selection of appropriate high-fat diet MASH models for lipid metabolism research.
