Abstract
The rise in the incidence of nonalcoholic steatohepatitis (NASH) has necessitated the development of an effective prevention methodology. An antidiabetic drug, belonging to the group of sodium glucose cotransporter 2 (SGLT2) inhibitors, has been tested for its therapeutic effect on NASH; however, no studies to date have demonstrated the preventive effect of an SGLT2 inhibitor on the histological progression of steatosis and fibrosis in a sequential manner in animal models. In the present study, we examined the effect of the SGLT2 inhibitor, tofogliflozin (Tofo), on NASH liver tissue using medaka as an animal model, maintaining a feeding amount and drug concentration in all animal bodies. We generated a medaka NASH model by feeding d‐rR/Tokyo medaka a high‐fat diet and administered Tofo by dissolving the drug directly in the water of the feeding tank. Thereafter, the effects of Tofo on body weight (BW), liver weight, hepatotoxicity, fatty infiltration, and fibrotic changes in the liver were examined. We report here that SGLT2 is expressed in medaka fish and that Tofo inhibits the accumulation of fatty tissue and delays the progression of liver fibrosis in the medaka NASH model by inhibiting increases in blood sugar, serum lipids, and transaminase, irrespective of changes in BW. These results suggest that Tofo is effective for treating NASH and that the medaka model may be useful for developing new therapeutic drugs for this disease.
Highlights
Ryo Goto1, Kenya Kamimura1, Yoko Shinagawa-Kobayashi1, Norihiro Sakai1, Takuro Nagoya1, Yusuke Niwa1, Masayoshi Ko1, Kohei Ogawa1, Ryosuke Inoue1, Takeshi Yokoo1, Akira Sakamaki1, Hiroteru Kamimura1, Satoshi Abe1, Hiroshi Nishina2 and Shuji Terai1
sodium glucose cotransporter 2 inhibitor (SGLT2I) are believed to contribute to nonalcoholic steatohepatitis (NASH) management [12]; the changes in liver histology over the course of treatment have been inconclusive in the murine model because SGLT2Is stimulate appetite, leading the mice to cope differently and exerting a different effect on the changes in body weight (BW); these may explain the individual differences in liver histology [13,17,19,27]
In this study, using a medaka NASH model, we investigated the effect of the Tofo, which has a higher specificity in inhibiting sodium glucose cotransporter 2 (SGLT2) [23], on the NASH liver to obtain new insights on the time-dependent effects of Tofo treatment and extensive quantitative changes in the liver histology and disease parameters, because in this model, we could maintain the serum concentration of the medicine by keeping them in the water of the averaged concentrated with medicines
Summary
We report here that SGLT2 is expressed in medaka fish and that Tofo inhibits the accumulation of fatty tissue and delays the progression of liver fibrosis in the medaka NASH model by inhibiting increases in blood sugar, serum lipids, and transaminase, irrespective of changes in BW. These results suggest that Tofo is effective for treating NASH and that the medaka model may be useful for developing new therapeutic drugs for this disease.
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