11β- hydroxysteroid dehydrogenase type 1 selective inhibitor alleviates insulin resistance and non-alcoholic fatty liver disease in db/db mice

Non-alcoholic fatty liver disease, often linked to insulin resistance, is associated with increased expression of 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) in liver tissue.We here assessed the effects of the 11-HSD1 inhibitor BVT.2733 on non-alcoholic fatty liver disease and its underlying mechanisms.Mice were divided into three groups: control, db/db, and db/db +BVT.2733.After 4 weeks, serological testing was conducted, and glucose tolerance and insulin sensitivity were assessed.The severity of non-alcoholic fatty liver disease was evaluated using B-ultrasound, Hematoxylin and Eosin staining, and Oil Red O staining.Liver corticosterone levels were measured using enzyme-linked immunosorbent assay.Liver expression of 11-HSD1, Phosphatidylinositol 3-kinase (PI3K) -Serine-Threonine kinase (AKT)-Mammalian target of rapamycin (mTOR) signaling pathway-related proteins, and autophagy-related proteins were analyzed by western blot.The results indicated that the leptin receptor-deficient mice db/db showed significant glucolipid metabolism disorder, insulin resistance, and increased non-alcoholic fatty liver disease severity, compared with the control group.BVT.2733 treatment ameliorated these conditions.Specifically, BVT.2733 downregulated liver 11-HSD1 expression, resulting in reduced liver corticosterone levels.Additionally, BVT.2733 enhanced hepatocyte autophagy, activated the PI3K-AKT signaling pathway and inhibited the mTOR signaling pathway.These findings suggest that BVT.2733 not only improves glucolipid metabolism and insulin resistance but also mitigates non-alcoholic fatty liver disease, in leptin receptor-deficient mice db/db.The underlying mechanism likely involves decreased liver corticosterone levels and enhanced hepatocyte autophagy, mediated by the PI3K-AKT and mTOR signaling pathways.