The diabetes medication Canagliflozin attenuates alcoholic liver disease by reducing hepatic lipid accumulation via SIRT1-AMPK-mTORC1 signaling pathway

Background and aims: Chronic consumption of large amounts of alcohol can lead to hepatic lipid accumulation and mitochondrial oxidative stress, resulting in alcoholic liver disease (ALD). Canagliflozin (Cana), an oral antidiabetic drug, regulates blood glucose by inhibiting sodium-glucose cotransporter-2 in renal tubulars, which also improves lipid metabolism and alleviates oxidative stress in hepatocyte. This study aims to determine the therapeutic effects of Cana on alcoholic liver injury and to explore the mechanistic pathways involved. Methods: C57BL/6J male mice at 8 weeks were used to construct a model of alcoholic fatty liver disease using the chronic-plus-binge alcohol feeding model. Primary hepatocytes and AML12 cell lines were used as in vitro models. The effects and mechanisms of Cana on alcoholic liver injury were investigated by using immunofluorescence, ELISA, H&E and Oil Red O staining, RT-PCR, and western blotting analysis. Results: Cana treatment reduced hepatic lipid accumulation, decreased glutathione and TNF-alpha levels, alleviated oxidative stress and inflammation. Mechanistic studies revealed that Cana reduced FAS expression in the liver, decreasing hepatic fatty acid synthesis, and increased PPAR alpha expression, promoting fatty acid oxidation. Additionally, Cana increased mitochondrial content and promoted mitophagy. These effects were mediated by the SIRT1-AMPK-mTORC1 signaling pathway. Conclusions: Cana activates the SIRT1-AMPK-mTORC1 signaling pathway, inhibiting alcohol-induced fatty acid synthesis, promoting fatty acid degradation, thereby alleviating alcoholic liver injury.