摘要：SummaryLipotoxicity plays an important role in the development of diabetic heart failure (HF). Canagliflozin (CAN), a marketed sodium-glucose co-transporter 2 inhibitor, has significantly beneficial effects on HF. In this study, we evaluated the protective effects and mechanism of CAN in the hearts of C57BL/6J mice induced by high-fat diet/streptozotocin (HFD/STZ) for 12 weeksin vivoand in HL-1 cells (a type of mouse cardiomyocyte line) induced by palmitic acid (PA)in vitro. The results showed that CAN significantly ameliorated heart functions and inflammatory responses in the hearts of the HFD/STZ-induced diabetic mice. CAN significantly attenuated the inflammatory injury induced by PA in the HL-1 cells. Furthermore, CAN seemed to bind to the mammalian target of rapamycin (mTOR) and then inhibit mTOR phosphorylation and hypoxia-inducible factor-1α (HIF-1α) expression. These results indicated that CAN might attenuate lipotoxicity in cardiomyocytes by inhibiting the mTOR/HIF-1α pathway and then show protective effects on diabetic hearts.Graphical abstractDisplay OmittedHighlights•Canagliflozin ameliorated heart dysfunctions in HFD/STZ-induced diabetic mice•Canagliflozin inhibited lipotoxicity in palmitic acid-induced HL-1 cardiomyocytes•mTOR-HIF-1α pathway mediated lipotoxicity in cardiomyocytes•Canagliflozin bound to mTOR and inhibited mTOR-HIF-1α pathwayHuman metabolism; Molecular biology
