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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>Tofo may be a potential candidate for inhibiting liver steatosis and fibrosis via an alternative pathway, unlike glucose metabolism, in NAFLD patients without diabetes.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月15日

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  • Yoshinori Ozono,
  • Hiroshi Kawakami,
  • Hiroshi Hatada,
  • Naomi Uchiyama,
  • Souichiro Ogawa,
  • Keisuke Uchida,
  • Hotaka Tamura,
  • Yuri Komaki,
  • Kenichi Nakamura,
  • Hisayoshi Iwakiri,
  • Satoru Hasuike,
  • Kenji Nagata

摘要

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.