The SGLT2 inhibitor empagliflozin negatively regulates IL-17/IL-23 axis-mediated inflammatory responses in T2DM with NAFLD via the AMPK/mTOR/autophagy pathway

Abstract

Empagliflozin is a SGLT2 inhibitor that reduces the concentration of blood glucose by inhibiting glucose reabsorption and promoting glucose excretion. Interestingly, empagliflozin also has some additional benefits, including cardiovascular protection, decreasing uric acid levels and improving NAFLD-related liver injury. However, the specific mechanism by which empagliflozin ameliorates NAFLD-related liver injury, especially how empagliflozin regulates hepatic immune inflammatory responses, is still unknown. In this study, male C57BL/6J mice were fed a high-fat diet and injected with streptozotocin to establish an animal model of T2DM with NAFLD. Then, diabetic mice with NAFLD were administered empagliflozin by gavage. We found that empagliflozin ameliorated liver injury and lipid metabolism disorder in T2DM mice with NAFLD. Empagliflozin significantly enhanced autophagy in hepatic macrophages via the AMPK/mTOR signalling pathway. After blocking autophagy and AMPK activity, empagliflozin could not prevent NAFLD-related liver injury. Furthermore, the expression levels of IL-17/IL-23 axis-related molecules were inhibited by empagliflozin through enhancing macrophage autophagy. Inhibition of IL-17/IL-23 axis activity attenuated liver injury in T2DM mice with NAFLD. In summary, these results suggested that empagliflozin could significantly ameliorate NAFLD-related liver injury, through enhancing hepatic macrophage autophagy via the AMPK/mTOR signalling pathway and further inhibiting IL-17/IL-23 axis-mediated inflammatory responses. This study provides a theoretical basis for the rational application of empagliflozin to treat T2DM with NAFLD and improve the quality of life of T2DM patients with NAFLD, which will have social benefits.