Preventive effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on diethylnitrosamine-induced liver tumorigenesis in obese and diabetic mice

// Koki Obara 1 , Yohei Shirakami 1, 2 , Akinori Maruta 1 , Takayasu Ideta 1 , Tsuneyuki Miyazaki 1 , Takahiro Kochi 1 , Hiroyasu Sakai 1 , Takuji Tanaka 3 , Mitsuru Seishima 2 and Masahito Shimizu 1 1 Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan 2 Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan 3 Department of Pathological Diagnosis, Gifu Municipal Hospital, Gifu, Japan Correspondence to: Yohei Shirakami, email: ys2443@gifu-u.ac.jp Keywords: sodium glucose cotransporter 2 (SGLT2), hepatocellular carcinoma (HCC), non-alcoholic fatty liver disease (NAFLD), obesity, diabetes mellitus Received: November 01, 2016 Accepted: March 11, 2017 Published: April 06, 2017 ABSTRACT Sodium glucose cotransporter 2 inhibitors are expected to ameliorate the abnormalities associated with metabolic syndrome including non-alcoholic fatty liver disease. In this study, we investigated the effects of the sodium glucose cotransporter 2 inhibitor tofogliflozin on the development of non-alcoholic fatty liver disease-related liver tumorigenesis in C57BL/KsJ-+Lepr db /+Lepr db obese and diabetic mice. The direct effects of tofogliflozin on human liver cancer cell proliferation were also evaluated. Mice were administered diethylnitrosamine-containing water for 2 weeks and were treated with tofogliflozin throughout the experiment. In mice treated with tofogliflozin, the development of hepatic preneoplastic lesions was markedly suppressed, and hepatic steatosis and inflammation significantly reduced, as evaluated using the non-alcoholic fatty liver disease activity score, in comparison with the control mice. Serum levels of glucose and free fatty acid and mRNA expression levels of pro-inflammatory markers in the liver were reduced by tofogliflozin treatment. Conversely, the proliferation of sodium glucose cotransporter 2 protein-expressing liver cancer cells was not inhibited by this agent. These findings suggest that tofogliflozin suppressed the early phase of obesity- and non-alcoholic fatty liver disease-related hepatocarcinogenesis by attenuating chronic inflammation and hepatic steatosis. Therefore, sodium glucose cotransporter 2 inhibitors may have a chemopreventive effect on obesity-related hepatocellular carcinoma.