Abstract
Cholesterol overloading-induced damages on hepatocytes cause liver dysfunctions, which further damages cholesterol metabolism and results in visceral fat accumulation in patients with type 2 diabetes mellitus (T2DM). The sodium-glucose cotransporter 2 (SGLT2) inhibitor Dapagliflozin has been reported to regulate cholesterol levels in T2DM patients, but the underlying mechanisms have not been studied. In the present study, we initially established in vivo T2DM mice models, and our results showed that both free cholesterol (FC) and cholesteryl ester (CE) were accumulated, while the pro-proliferation associated genes were downregulated in T2DM mice liver tissues, which were reversed by Dapagliflozin co-treatment. Similarly, the mice primary hepatocytes were loaded with cholesterol to establish in vitro models, and we expectedly found that Dapagliflozin attenuated cholesterol-overloading induced cytotoxicity and cellular senescence in the hepatocytes. Then, we noticed that oxidative damages occurred in T2DM mice liver tissues and cholesterol treated hepatocytes, which could be suppressed by Dapagliflozin. Also, elimination of Reactive Oxygen Species (ROS) by N-acetyl-L-cysteine (NAC) recovered cellular functions of hepatocytes in vitro and in vivo. Furthermore, the potential underlying mechanisms were uncovered, and our data suggested that Dapagliflozin activated the anti-oxidant Nrf2/HO-1 pathway in mice hepatocytes, and silencing of Nrf2 abrogated the protective effects of Dapagliflozin on cholesterol-overloaded hepatocytes. Collectively, we concluded that Dapagliflozin recovered cholesterol metabolism functions in T2DM mice liver via activating the anti-oxidant Nrf2/HO-1 pathway, and our data supported that Dapagliflozin was a potential therapeutic drug to eliminate cholesterol-induced cytotoxicity during T2DM pathogenesis.