Semaglutide ameliorates diabetes-induced steatotic liver disease in rats: Role of AMPK, mTOR, ERK and ABHD6

Purpose: To determine whether semaglutide protects rats with diabetes from metabolic dysfunction-associated steatotic liver disease (MASLD), and its underlying molecular mechanisms. Methods: Fifty-three male Wistar rats were divided into five groups: control, streptozotocin (STZ, 45 mg/kg given intraperitoneally); STZ + low-dose semaglutide (12 μg/kg every 3 days), STZ + high-dose semaglutide (40 μg/kg every 3 days), and STZ + metformin (100 mg/kg/day orally). Rats (except control group) were given 10 % fructose in drinking water from the beginning of the experiment until the 12th week. Blood concentrations of glucose, insulin, liver biomarkers, and lipid profiles were measured. Oxidative stress and inflammatory markers in liver tissues were assessed, along with protein expressions of pAMPK, mTOR, ERK, and ABHD6. Results: High-dose semaglutide enhanced blood glucose levels, reduced feed and water intake, decreased body weight, and enhanced liver function, when compared to the STZ group. Oxidative stress was reduced, and levels of inflammatory indices (TNF-α and IL-6) were supressed. Additionally, semaglutide decreased the expression levels of mTOR, ERK, and ABHD6, while activating the hepatic AMPK pathway. Reduced histopathological lesions were observed in liver tissues. Conclusion: Semaglutide may be beneficial in preventing MASLD in T2DM, thereby providing new perspectives on its potential therapeutic role.