Abstract
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates hepatic glucose output and systemic glucose homeostasis. We aimed to investigate the anti-fibrotic effect of a novel 11β-HSD1 inhibitor in a liver fibrosis mouse model. Hepatic fibrosis animal model was induced by thioacetamide administration during 19 weeks. Bulk RNA sequencing was performed to evaluate mode of action. Changes of immune cell distribution was evaluated using mass cytometry in peripheral blood. 11β-HSD1 inhibitor treatment group showed a significant decrease in the fibrosis area and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with the thioacetamide induced hepatic fibrosis animal model. Bulk RNA sequencing data showed Notch signal decreased and natural killer (NK) cell pathway increased after 11β-HSD1 inhibitor treatment. Changes of NK cell population was reconfirmed by mass cytometry in In Vivo animal models, and expression of Notch ligands (Jag2, Dll1, Dll3, and Dll4), Notch signals (Hes1 and Sox9), and Notch receptors (Notch3 and Notch4) decreased after 11β-HSD1 inhibitor treatment. Therefore, the novel 11β-HSD1 inhibitor ameliorates liver fibrosis by inhibiting the Notch signaling pathway and increasing the NK cell population.