A high-fat/high-sucrose/high-cholesterol diet leads to early indications of metabolic dysfunction-associated steatohepatitis-like lesions in obese diabetic mice.

Chronic hyperlipidemia and/ or hyperglycemia can impair various organs, such as the liver, kidney, and pancreas, through metabolic abnormalities. Metabolic dysfunction-associated steatohepatitis (MASH), related from nonalcoholic steatohepatitis (NASH), exhibits complex pathophysiological features, and animal models of MASH are essential for elucidating its underlying mechanisms. This study aimed to induce MASH-like lesions in obese type 2 diabetic mice by feeding them a high-fat/high-sucrose/high-cholesterol (HFSC) diet. C57BL/6J, db/db, and KK-Ay mice at 6 weeks of age were fed an HFSC diet for 8 weeks. Collected samples were subjected to hematobiochemical, gene expression, and histopathological analyses. At 14 weeks of age, both diabetic mouse models showed hyperglycemia and hyperlipidemia, with hypercholesterolemia observed in HFSC-fed groups. HFSC-fed db/db and KK-Ay mice showed increased hepatic steatosis, and KK-Ay mice also showed partial hepatic fibrosis in pericentral venous and perivascular areas. mRNA analysis revealed upregulation of hepatic genes involved in lipid synthesis, inflammation, and fibrosis in diabetic mice fed the HFSC diet. Obese type 2 diabetic mice fed a high-fat/high-sucrose/high-cholesterol diet showed early indications of MASH-like lesions, supporting their utility as MASH animal models.