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

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

doi:10.1186/s12876-026-04610-1

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

BMC Gastroenterol. 2026 Jan 15;26(1):108. doi: 10.1186/s12876-026-04610-1.

Affiliations

¹ Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kihara, Kiyotake, Miyazaki, 5200, 889-1601, Japan.
² Division of Gastroenterology and Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kihara, Kiyotake, Miyazaki, 5200, 889-1601, Japan. hiropon@med.miyazaki-u.ac.jp.

^# Contributed equally.

Abstract

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.

Keywords: CDAHFD; Diabetes; NAFLD; NASH; Tofogliflozin.

MeSH terms

Animals
Benzhydryl Compounds* / pharmacology
Benzhydryl Compounds* / therapeutic use
Choline Deficiency / complications
Diet, High-Fat
Disease Models, Animal
Glucosides* / pharmacology
Glucosides* / therapeutic use
Liver / drug effects
Liver / metabolism
Liver / pathology
Liver Cirrhosis* / drug therapy
Liver Cirrhosis* / etiology
Liver Cirrhosis* / prevention & control
Male
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease* / drug therapy
Non-alcoholic Fatty Liver Disease* / etiology
Non-alcoholic Fatty Liver Disease* / metabolism
Non-alcoholic Fatty Liver Disease* / pathology
Sodium-Glucose Transporter 2 Inhibitors* / pharmacology
Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use

Substances

Glucosides
Sodium-Glucose Transporter 2 Inhibitors
6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol
Benzhydryl Compounds