Tofogliflozin attenuates liver steatosis and fibrosis in non-diabetic non-alcoholic steatohepatitis mice

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease with increasing global prevalence. Although diabetes is a major factor in NAFLD progression, up to 75% of the patients with NAFLD do not have diabetes. Tofogliflozin (Tofo), a sodium-glucose cotransporter type-2 inhibitor, is widely used in patients with type 2 diabetes. Several clinical trials with Tofo have shown its beneficial effects in NAFLD patients with diabetes; however, currently, there are limited data on NAFLD patients without diabetes. METHODS: C57Bl/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) as a model of non-diabetic non-alcoholic steatohepatitis (NASH). The mice were fed either a normal diet or CDAHFD for 12 weeks, and received either vehicle or Tofo based on their assigned group for 12 weeks. RESULTS: Tofo treatment attenuated CDAHFD-induced liver steatosis and fibrosis. The percentage of monocyte-derived macrophages in the liver, which was significantly increased in the CDAHFD-fed mice, was reduced by Tofo treatment. Furthermore, Tofo treatment increased the hepatic protein and mRNA expression levels related to fatty acid oxidation, which was decreased in CDAHFD-fed mice. Additionally, Tofo treatment decreased the hepatic protein and mRNA expression levels related to fatty acid synthesis, which was increased in CDAHFD-fed mice. CONCLUSION: Tofo may be a potential candidate for inhibiting liver steatosis and fibrosis via an alternative pathway, unlike glucose metabolism, in NAFLD patients without diabetes.