1632-P: Wild-Derived Chromosome 1 Substitution Strains—Unveiling Novel Insights into NASH Research

Metabolic diseases, encompassing obesity, NASH, and diabetes, result from a complex interplay of factors, including genetics, lifestyle, and environment. However, conventional mouse models induced by diet or with single genetic alterations often fall short in accurately representing human metabolic diseases. In contrast to laboratory mice, wild mice exhibit a greater diversity of genetic polymorphisms, adapting to their natural environments. To enhance model fidelity, we created 11 wild-derived Chr1 substitution strains by replacing C57BL/6 mice's Chr1 with that from wild mice across 11 Chinese regions. Through phenotype screening, we identified 4 strains displaying spontaneously obesity and hepatic steatosis under chow diet. Notably, one strain named B6-Chr1^KM mice displayed obvious obesity-related NASH phenotype (the total score of NAS was over 5).Transcriptomics analysis of the B6-Chr1^KM liver tissue revealed unique gene expression patterns. KEGG analysis highlighted NASH-related pathways, including "Arachidonic acid metabolism." 398 genes specific to B6-Chr1^KM were identified, with PPI analysis pinpointing top 10 hub genes as potential NASH research targets. In summary, our wild-derived Chr1 substitution strains provide valuable tools for metabolic disease study. B6-Chr1^KM mice, in particular, offer a novel perspective for NASH research.