A preclinical model of severe NASH-like liver injury by chronic administration of a high-fat and high-sucrose diet in mice

• Published in: Toxicology and applied pharmacology 2024-10, Vol.491, p.117046-117046, Article 117046
• Main Authors: Willett, Rose A., Tryndyak, Volodymyr P., Hughes Hanks, Jennifer M., Elkins, Lana, Nagumalli, Suresh K., Avigan, Mark I., Ross, Sharon A., da Costa, Gonçalo Gamboa, Beland, Frederick A., Rusyn, Ivan, Pogribny, Igor P.
• Format: Article
• Language: English
• Subjects: Animals; Collaborative cross; Diet, High-Fat - adverse effects; Dietary Sucrose - adverse effects; Disease Models, Animal; Disease Progression; Female; Lipid Metabolism - drug effects; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Cirrhosis - chemically induced; Liver Cirrhosis - pathology; Male; Mice; Non-alcoholic fatty liver disease (NAFLD); Non-alcoholic Fatty Liver Disease - pathology; Non-alcoholic steatohepatitis (NASH); Obesogenic diet; Preclinical mouse model
• ISSN: 0041-008X; 1096-0333; 1096-0333
• DOI: 10.1016/j.taap.2024.117046

Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease, affecting 38% of adults globally. If left untreated, NAFLD may progress to more advanced forms of the disease, including non-alcoholic steatohepatitis (NASH), liver cirrhosis, and fibrosis. Early NAFLD detection is critical to prevent disease progression. Using an obesogenic high-fat and high-sucrose (HF/HS) diet, we characterized the progression of NAFLD in male and female Collaborative Cross CC042 mice after 20-, 40-, and 60-week intervals of chronic HF/HS diet feeding. The incidence and severity of liver steatosis, inflammation, and fibrosis increased in both sexes over time, with male mice progressing to a NASH-like disease state faster than female mice, as indicated by earlier and more pronounced changes in liver steatosis. Histopathological indication of macrovesicular steatosis and gene expression changes of key lipid metabolism genes were found to be elevated in both sexes after 20 weeks of HF/HS diet. Measurement of circulating markers of inflammation (CXCL10 and TNF-α), histopathological analysis of immune cell infiltrates, and gene expression changes in inflammation-related genes indicated significant liver inflammation after 40 and 60 weeks of HF/HS diet exposure in both sexes. Liver fibrosis, as assessed by Picosirius red and Masson's trichrome staining and changes in expression of key fibrosis related genes indicated significant changes after 40 and 60 weeks of HF/HS diet exposure. In conclusion, we present a preclinical animal model of dietary NAFLD progression, which recapitulates human pathophysiological and pathomorphological changes, that could be used to better understand the progression of NAFLD and support development of new therapeutics. •Chronically feeding mice a high-fat and high-sucrose diet induced changes consistent with clinical NAFLD.•The model exhibits histological indication of steatosis, inflammation, and fibrosis in both sexes.•Gene expression changes support NASH-like histopathological progression.•This preclinical NASH model could be used for future drug therapy studies.