A diet-driven metabolic dysfunction-associated steatohepatitis (MASH) mouse model resembles the corresponding human disease

Most of the available preclinical Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) models fail to resemble metabolic comorbidities and liver fibrosis. To establish a standard MASLD/MASH model, we characterized some morphological, biochemical, and transcriptomic features in a Western diet-induced MASLD model in mice, depicting its similarities to the corresponding human disease. Male C57BL/6J mice received a hypercaloric diet containing sucrose, saturated fat, and cholesterol-rich chow, and high sugar solution for 24 weeks. This model featured a distinct MASH phenotype with obesity, impaired glucose metabolism, hypercholesterolemia, extensive macro and microvesicular, liver steatosis, and slight-to-moderate pericellular/perisinusoidal fibrosis, which was in keeping with the increased hepatic levels of IL-6 and TNF-α, and upregulation of 18 collagen subunit genes (as Col1a1, Col1a2, Col3a1, Col5a2, Col4a1, Col6a3, Col14a1, Col6a2, Col5a1), 34 cytokines or chemokines or related receptors-coding genes (as Il15, Cxcl9, Ccl22), 18 TNF-related genes (as Tnfaip8l3, Tnfrsf21, Tnfaip8, Tnfrfs12a) and 12 metalloproteinase/tissue inhibitors of metalloproteinases-related genes (as Mmp2, Mmp7). The downregulated genes were negative regulators of gluconeogenesis, insulin secretion, and lipid biosynthesis, most belonging to the major urinary protein (MUP) family. The computational analysis of human samples revealed a similarity between our bioassay and human steatohepatitis, with the upregulation of fibrosis- and inflammation-associated orthologs (COL1A1, COL1A2, COL3A1, COL5A2, COL4A1, COL6A3, COL14A1, COL6A2, COL5A1, TNFAIP8L3, TNFRSF21, TNFAIP8, TNFRFS12A, IL15, CXCL9, CCL22, MMP2, MMP7). Our mouse model may be applied as a standard MASH translational bioassay, providing valuable insights into the inflammatory/fibrosis axis of this chronic disease, from the pathogenesis to therapeutic intervention.