Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH

Kumiko Shiba,Kentaro Mori,Naomi Ogasawara,Chikara Komiya,Shinobu Yamaguchi,Michiko Itoh,Takayoshi Suganami,Yasutaka Miyachi,Noriko Shimazu,Makoto Katoh,Yoshihiro Ogawa,Kyoichiro Tsuchiya

doi:10.1038/s41598-018-19658-7

Abstract

Sodium glucose cotransporter 2 (SGLT2) inhibitors, an antidiabetic drug, promotes urinary excretion of glucose by blocking its reabsorption in the renal proximal tubules. It is unclear whether SGLT2 inhibition could attenuate nonalcoholic steatohepatitis (NASH) and NASH-associated hepatocellular carcinoma. We examined the preventive effects of an SGLT2 inhibitor canagliflozin (CANA) in Western diet (WD)-fed melanocortin 4 receptor-deficient (MC4R-KO) mice, a mouse model of human NASH. An eight-week CANA treatment attenuated hepatic steatosis in WD-fed MC4R-KO mice, with increased epididymal fat mass without inflammatory changes. CANA treatment for 20 weeks inhibited the development of hepatic fibrosis in WD-fed MC4R-KO mice. After one year of CANA treatment, the number of liver tumors was significantly reduced in WD-fed MC4R-KO mice. In adipose tissue, CANA suppressed the ratio of oxidative to reduced forms of glutathiones (GSSG/GSH) in WD-fed MC4R-KO mice. Treatment with GSH significantly attenuated the H2O2-induced upregulation of genes related to NADPH oxidase in 3T3-L1 adipocytes, and that of Il6, Tgfb, and Pdgfb in RAW264.7 cells. This study provides evidence that SGLT2 inhibitors represent the unique class of drugs that can attenuate or delay the onset of NASH and eventually hepatocellular carcinoma, at least partly, through “healthy adipose expansion”.

Highlights

In recent decades, metabolic syndrome has become increasingly prevalent, with an increased incidence of nonalcoholic fatty liver disease (NAFLD)[1,2]
Here we demonstrate that an Sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (CANA) attenuates the development of hepatocellular carcinoma, as well as hepatic steatosis, inflammation, and fibrosis
We examined whether CANA inhibits the development of insulin resistance- and obesity-associated metabolic phenotypes in MC4R-KO mice on a western diet (WD) feeding regimen

Summary

Introduction

Metabolic syndrome has become increasingly prevalent, with an increased incidence of nonalcoholic fatty liver disease (NAFLD)[1,2]. We recently reported that the SGLT2 inhibitor ipragliflozin promotes fat accumulation in epididymal fat without deteriorating adipose inflammation and prevents ectopic fat accumulation in the liver[18] This suggests that SGLT2 inhibitors prevent hepatic steatosis via its insulin-independent glucose-lowering effect and caloric loss and via modulating energy homeostasis and balance in adipose and non-adipose tissues. We have developed an experimental mouse model of NASH; melanocortin 4 receptor-deficient (MC4R-KO) mice fed a western diet (WD) develop a liver condition like human NASH, in association with obesity, insulin resistance, and dyslipidemia[19] Using these mice, here we demonstrate that an SGLT2 inhibitor canagliflozin (CANA) attenuates the development of hepatocellular carcinoma, as well as hepatic steatosis, inflammation, and fibrosis. Our findings with the MC4R-KO mice suggest that SGLT2 inhibitors have a significant clinical impact on human NASH and NASH-associated hepatocellular carcinoma

Methods

Results

Conclusion