Superior inflammatory response and MASH progression in Apoe-/- mice compared to wild-type mice: a comprehensive time-course analysis

Background Metabolic dysfunction-associated steatohepatitis (MASH) represents a critical progression of metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by hepatic steatosis, inflammation, and beginning fibrosis. The selection of appropriate animal models is crucial for understanding disease mechanisms and evaluating therapeutic interventions. While wild-type C57BL/6 mice are widely used, hyperlipidemic apolipoprotein E-deficient ( Apoe -/- ) mice may offer superior disease modeling capabilities. This study compared the development and progression of diet-induced MASH in Apoe -/- mice versus wild-type C57BL/6J mice over multiple time points, with a focus on inflammatory responses and histological changes. Methods Male wild-type C57BL/6J and male Apoe -/- mice were fed either standard chow diet or high-fat/high-fructose (Hf/Hf) diet for 8, 12, 16, or 24 weeks. Comprehensive analyses included histological evaluation, MRS based fat quantification, immunohistochemistry, serum biochemistry, cytokine profiling, trace element analysis, oxylipin profiling by UPLC-MS/MS, intestinal barrier function assessment, and gene expression analysis. Results Apoe -/- mice showed markedly accelerated MASH development compared to wild-type mice. Notably, Apoe -/- mice fed Hf/Hf diet for 12 weeks exhibited substantially greater inflammatory infiltration than wild-type mice even after 24 weeks of Hf/Hf diet. This enhanced inflammatory response was accompanied by increased infiltration of macrophages (CD68 + cells), elevated levels of pro-inflammatory cytokines, altered trace element homeostasis, and dysregulated oxylipin profiles favoring pro-inflammatory mediators. There was also evidence of compromised intestinal barrier function and more pronounced histological features of MASH, includinGSTeatosis, lobular inflammation and hepatocyte ballooning. Conclusion Apoe -/- mice represent ASuperior model for MASH research, demonstrating accelerated disease progression and enhanced inflammatory responses compared to the wild-type mice. The rapid and robust inflammatory phenotype in Apoe -/- mice provides a more efficient and clinically relevant model for investigating MASH pathogenesis and testing therapeutic interventions.