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

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

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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".

Original languageEnglish
Article number2362
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

All Science Journal Classification (ASJC) codes

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    Shiba, K., Tsuchiya, K., Komiya, C., Miyachi, Y., Mori, K., Shimazu, N., Yamaguchi, S., Ogasawara, N., Katoh, M., Itoh, M., Suganami, T., & Ogawa, Y. (2018). Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH. Scientific reports, 8(1), [2362]. https://doi.org/10.1038/s41598-018-19658-7