Hepatic and osteogenic effects of dulaglutide and semaglutide in an acute model of hepatotoxicity in mice

Hepatic liver diseases are among the most common chronic diseases worldwide, with few available treatments. Bone diseases, such as osteoporosis, are associated with liver disease and other conditions and represent another challenge to treatment. The present study investigated effects of the antidiabetic glucagon-like peptide 1 (GLP-1) analogs semaglutide and dulaglutide on hepatic and osteogenic parameters in an acute CCl₄-induced hepatotoxicity model. Two protocols were used in male Swiss mice: treatment and pretreatment with one or two administrations of semaglutide (0.021 mg/kg, i.p.), dulaglutide (0.014 mg/kg, i.p.), silymarin (100 mg/kg, p.o., positive control), or vehicle (10 ml/kg, i.p.). The mice were euthanized 48 h after the challenge with 1.5 % CCl₄ (0.25 ml, i.p.). The results indicated that dulaglutide exerted greater hepatoprotective effects than semaglutide, reducing liver necrosis, hepatic glutathione-S-transferase activity, and plasma alanine aminotransferase levels. Semaglutide improved the biliary excretion of cholesterol, benefiting more the biliary system than the hepatic parenchyma. Both drugs induced the gene expression of Cyclin D1, improving the proliferative phase of liver regeneration. With regard to bone remodeling, semaglutide increased the osteoblast surface (O.b/S) and its function by increasing the osteoid surface (OS/BS), suggesting an increase in bone formation. These data indicate that dulaglutide has potential as an alternative treatment for hepatotoxicity that is mainly induced by drugs, and semaglutide can improve bone development, demonstrating the potential of this GLP-1 analog for the prevention of bone fragility that is related to liver diseases.