Canagliflozin ameliorates hepatic fat deposition in obese diabetic mice: Role of prostaglandin E2

Clinical and animal studies have suggested a possible beneficial effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on nonalcoholic fatty liver disease (NAFLD) including nonalcoholic steatohepatitis (NASH). Although SGLT2 inhibitors have been shown to reduce hepatic fat deposition in association with loss of body weight, the mechanism of this action has remained unknown. We here show that the SGLT2 inhibitor canagliflozin ameliorated fatty liver and hyperglycemia without affecting body weight or epididymal fat weight in obese diabetic KKAy mice. Lipidomics analysis based on liquid chromatography and tandem mass spectrometry revealed that canagliflozin treatment increased the amounts of prostaglandin E2 (PGE(2)) and resolvin E3 in the liver of these mice. We also found that PGE(2) attenuated fat deposition in mouse primary hepatocytes exposed to palmitic acid. Our results thus suggest that PGE(2) may play an important role in the amelioration of hepatic fat deposition by canagliflozin, with elucidation of its mechanism of action potentially providing a basis for the development of new therapeutics for NAFLD-NASH. (C) 2021 Elsevier Inc. All rights reserved.