Dapagliflozin attenuates steatosis in livers of high-fat diet-induced mice and oleic acid-treated L02 cells via regulating AMPK/mTOR pathway

Dapagliflozin (DAPA), a kind of sodium-glucose cotransporter 2(SGLT2) inhibitor is used to treat diabetes mellitus by inhibiting urine glucose reuptake. Recent clinical outcomes indicate that SGLT2 inhibitors may exert pharmacological activities against non-alcoholic fatty liver diseases. Nonetheless, the underlying molecular mechanisms are still poorly elucidated. In this study, we investigated the potential anti-fatty liver effects of DAPA in vivo and in vitro and assayed their underlying mechanisms. Male NIH (National Institutes of Health) mice were fed with a high-fat diet (HFD) and then treated with DAPA by gavage for 4 weeks. In the following experiments, L02 cells were treated with oleic acid (OA) and different concentrations of DAPA to assess lipid metabolism. Our results revealed that DAPA administration could remarkably suppress excessive fat accumulation in the liver tissues of HFD-fed mice and OA-treated L02 cells. Importantly, DAPA could downregulate the expression levels of proteins related to lipid synthesis and upregulate the expression levels of genes associated with fatty acid oxidation in vitro and in vivo. We also found that DAPA intervention could activate adenosine monophosphate-activated protein kinase (AMPK) phosphorylation but inhibit mammalian target of rapamycin (mTOR) phosphorylation in vitro and in vivo. AMPK activation might be mediated by increasing liver kinase B1 activity and decreasing ATP level. Furthermore, these ameliorative effects were completely eliminated by an AMPK inhibitor, compound C. This study suggested that DAPA might remarkably ameliorate hepatic steatosis mediated through the AMPK/mTOR pathway and thus could be a potential drug candidate for the treatment of fatty liver diseases.