DIO-MASH mice analysed for hepatic gene expression after treatment with semaglutide
Modulation of metabolic, inflammatory, and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease strongly associated with cardiometabolic risk factors. Semaglutide, a glucagon-like peptide-1 receptor agonist, improves liver histology in MASH, but the underlying signals and pathways driving semaglutide-induced MASH resolution are not well understood. We show that, in two preclinical MASH models, semaglutide improved histological markers of fibrosis and inflammation, and reduced hepatic expression of fibrosis- and inflammation-related gene pathways. Overall design: DIO-MASH mice were analysed for hepatic gene expression after treatment with semaglutide. C57BL/6JRj mice (5–6 weeks old) were obtained from Janvier Labs (Le Genest Saint Isle, France) and housed in a controlled environment (12-h light/dark cycle, 21 ± 2.0°C, humidity 50 ± 10%). Mice had ad libitum access to tap water and Gubra Amylin NASH diet (4.49 kcal/g, 40 kcal-% fat; of these, 46% saturated fatty acids by weight, 22% fructose, 10% sucrose, 2% cholesterol; D09100310, Research Diets) for 34 weeks for the efficacy trial. A group was maintained on regular mouse chow (2.85 kcal/g, Altromin 1324, Brogaarden, Hoersholm, Denmark) for comparison. A liver biopsy was taken from the mice 4 weeks before treatment start. After the procedure, animals were single-housed and allowed to recover for 4 weeks prior to treatment start. Only mice with steatosis score 3 or mice with fibrosis score >1 and steatosis score >2 were included. Included animals were then randomized into treatment groups based on mean baseline PSR area% one week before dose start. Mice were administered vehicle or semaglutide 123 µg/kg for 8, 16, or 24 weeks. Vehicle-dosed chow-fed mice and mice switched to chow and dosed with vehicle served as additional controls. Dosing was performed subcutaneously once daily in a volume of 5 ml/kg. To reduce initial gastric discomfort, the dose was increased through daily increments until reaching the target dose on treatment day 5.