Canagliflozin, an SGLT2 Inhibitor, Prevents Development of Hepatocellular Carcinoma (HCC) from Nonalcoholic Steatohepatitis (NASH) in a Mouse Model of NASH-HCC Under Diabetic State

Abstract

Nonalcoholic steatohepatitis (NASH) can result in liver cirrhosis and hepatocellular carcinoma (HCC). Several studies have shown that some SGLT2 inhibitors alleviate hepatic steatosis or steatohepatitis in type 2 diabetic mice or rats. First, we investigated the effects of canagliflozin (CANA), an SGLT2 inhibitor, on steatohepatitis and fibrosis in a novel diabetes nonalcoholic steatohepatitis (NASH) -HCC progression model mice. We next investigated inhibitory effects of CANA on development of HCC in this model mice. Mice aged 5 weeks were divided into two groups (vehicle and CANA 30 mg/kg) and fed for 3 more weeks. The histological nonalcoholic fatty liver disease activity score (NAS) was lower in the CANA group than in the vehicle group. The expression of type 1 and 3 collagen mRNA was reduced in the CANA group. Mice aged 5 weeks were divided into three groups of 9 animals: vehicle, CANA initial administration 30mg/kg (5 to 9 W), CANA continuous administration 30 mg/kg (5 to 16W). At the age of 16 weeks, the NAS was significantly lower in the CANA continuous administration group than in the vehicle or the CANA initial administration groups. The number of hepatic tumors was significantly smaller in the CANA continuous administration group than in the vehicle group. Immunohistochemistry showed that expression of glutamine synthetase, a marker of HCC, was reduced in the CANA continuous administration group compared with the vehicle group. Furthermore, the CANA continuous administration significantly decreased expression of mRNAs for α-fetoprotein, a tumor maker of HCC, compared with the vehicle administration. In conclusion, canagliflozin attenuates development of NASH showing anti-steatotic and anti-inflammatory effects, and prevents progression of HCC from NASH. Disclosure T. Jojima: Research Support; Self; mitsubishi tanabe phama corporation. S. Wakamatu: None. T. Iijima: None. I. Usui: None. Y. Aso: None.