Abstract
The aim of the present study is to investigate the effects of canagliflozin, a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, on non-alcoholic steatohepatitis (NASH) and NASH-related hepatocellular carcinoma (HCC) in a mouse model of diabetes and NASH-HCC. First, mice aged five weeks were divided into two groups (vehicle group and canagliflozin group) and were treated for three weeks. Then, mice aged five weeks were divided into three groups of nine animals each: the vehicle group, early canagliflozin group (treated from five to nine weeks), and continuous canagliflozin group (treated from five to 16 weeks). Canagliflozin was administered at a dose of 30 mg/kg in these experiments. In addition, the in vitro effects of canagliflozin were investigated using HepG2 cells, a human HCC cell line. At the age of eight or 16 weeks, the histological non-alcoholic fatty liver disease activity score was lower in the canagliflozin-treated mice than in vehicle-treated mice. There were significantly fewer hepatic tumors in the continuous canagliflozin group than in the vehicle group. Immunohistochemistry showed significantly fewer glutamine synthetase-positive nodules in the continuous canagliflozin group than in the vehicle group. Expression of α-fetoprotein mRNA, a marker of HCC, was downregulated in the continuous canagliflozin group when compared with the vehicle group. At 16 weeks, there was diffuse SGLT1 expression in the hepatic lobules and strong expression by hepatocytes in the vehicle group, while SGLT2 expression was stronger in liver tumors than in the lobules. In the in vitro study, canagliflozin (10 μM) suppressed the proliferation of HepG2 cells. Flow cytometry showed that canagliflozin reduced the percentage of HepG2 cells in the G2/M phase due to arrest in the G1 phase along with decreased expression of cyclin D and Cdk4 proteins, while it increased the percentage of cells in the G0/1 phase. Canagliflozin also induced apoptosis of HepG2 cells via activation of caspase 3. In this mouse model of diabetes and NASH/HCC, canagliflozin showed anti-steatotic and anti-inflammatory effects that attenuated the development of NASH and prevented the progression of NASH to HCC, partly due to the induction of cell cycle arrest and/or apoptosis as well as the reduction of tumor growth through the direct inhibition of SGLT2 in tumor cells.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most common cancer overall and the third leading cause of cancer-related death worldwide [1]
We recently reported that the sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin improves hepatic steatosis in patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD), and attenuates liver fibrosis in patients with significant fibrosis [11], suggesting that SGLT2 inhibitors have an anti-fibrotic effect on human Non-alcoholic steatohepatitis (NASH)
The present study demonstrated that treatment with canagliflozin prevented the development of NASH in a mouse model of diabetes with NASH/HCC
Summary
Hepatocellular carcinoma (HCC) is the sixth most common cancer overall and the third leading cause of cancer-related death worldwide [1]. Several studies have examined the impact of sodium-glucose co-transporter 2 (SGLT2) inhibitors on the occurrence of non-alcoholic fatty liver disease (NAFLD) and/or NASH in rodent models and humans [5,6,7,8,9]. We previously reported that the SGLT2 inhibitor empagliflozin showed anti-steatotic and anti-inflammatory effects [5], which suppressed the development of NASH in a mouse model of diabetes and NASH/cirrhosis/HCC (the STAM mouse) [10]. This mouse model progresses from diabetes with NAFLD to NASH by eight weeks of age and HCC develops at 16 weeks [10]. No studies have examined whether SGLT2 inhibitors can prevent the progression of NASH to hepatocarcinogenesis
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