NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China.
NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin 300134, China.
Int Immunopharmacol. 2021 May;94:107492. doi: 10.1016/j.intimp.2021.107492. Epub 2021 Feb 26.
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.
恩格列净是一种 SGLT2 抑制剂，通过抑制葡萄糖重吸收和促进葡萄糖排泄来降低血糖浓度。有趣的是，恩格列净还有一些额外的益处，包括心血管保护、降低尿酸水平和改善非酒精性脂肪性肝病（NAFLD）相关的肝损伤。然而，恩格列净改善 NAFLD 相关肝损伤的确切机制，特别是恩格列净如何调节肝免疫炎症反应，尚不清楚。在这项研究中，雄性 C57BL/6J 小鼠喂食高脂肪饮食并注射链脲佐菌素，建立了伴有 NAFLD 的 2 型糖尿病动物模型。然后，用恩格列净灌胃糖尿病伴 NAFLD 的小鼠。我们发现，恩格列净改善了伴有 NAFLD 的 2 型糖尿病小鼠的肝损伤和脂质代谢紊乱。恩格列净通过 AMPK/mTOR 信号通路显著增强了肝巨噬细胞的自噬。阻断自噬和 AMPK 活性后，恩格列净不能预防 NAFLD 相关的肝损伤。此外，恩格列净通过增强巨噬细胞自噬抑制了 IL-17/IL-23 轴相关分子的表达。抑制 IL-17/IL-23 轴活性可减轻伴有 NAFLD 的 2 型糖尿病小鼠的肝损伤。总之，这些结果表明，恩格列净通过增强 AMPK/mTOR 信号通路介导的肝巨噬细胞自噬，并进一步抑制 IL-17/IL-23 轴介介导的炎症反应，显著改善了伴有 NAFLD 的 2 型糖尿病相关的肝损伤。本研究为恩格列净合理应用于治疗伴有 NAFLD 的 2 型糖尿病和提高伴有 NAFLD 的 2 型糖尿病患者的生活质量提供了理论依据，具有一定的社会效益。
