The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis–associated liver tumors in a novel murine model

Naoki Yoshioka, Miyako Tanaka, Kozue Ochi, Akiko Watanabe, Kenji Ono, Makoto Sawada, Tomoo Ogi, Michiko Itoh, Ayaka Ito, Yukihiro Shiraki, Atsushi Enomoto, Masatoshi Ishigami, Mitsuhiro Fujishiro, Yoshihiro Ogawa, Takayoshi Suganami

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Abstract

Background: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. Methods: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. Findings: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. Interpretation: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.

Original languageEnglish
Article number111738
JournalBiomedicine and Pharmacotherapy
Volume140
DOIs
Publication statusPublished - Aug 2021

All Science Journal Classification (ASJC) codes

  • Pharmacology

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