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Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH
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 car...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799179/ https://www.ncbi.nlm.nih.gov/pubmed/29402900 http://dx.doi.org/10.1038/s41598-018-19658-7 |
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author | Shiba, Kumiko Tsuchiya, Kyoichiro Komiya, Chikara Miyachi, Yasutaka Mori, Kentaro Shimazu, Noriko Yamaguchi, Shinobu Ogasawara, Naomi Katoh, Makoto Itoh, Michiko Suganami, Takayoshi Ogawa, Yoshihiro |
author_facet | Shiba, Kumiko Tsuchiya, Kyoichiro Komiya, Chikara Miyachi, Yasutaka Mori, Kentaro Shimazu, Noriko Yamaguchi, Shinobu Ogasawara, Naomi Katoh, Makoto Itoh, Michiko Suganami, Takayoshi Ogawa, Yoshihiro |
author_sort | Shiba, Kumiko |
collection | PubMed |
description | 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 H(2)O(2)-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”. |
format | Online Article Text |
id | pubmed-5799179 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57991792018-02-14 Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH Shiba, Kumiko Tsuchiya, Kyoichiro Komiya, Chikara Miyachi, Yasutaka Mori, Kentaro Shimazu, Noriko Yamaguchi, Shinobu Ogasawara, Naomi Katoh, Makoto Itoh, Michiko Suganami, Takayoshi Ogawa, Yoshihiro Sci Rep Article 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 H(2)O(2)-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”. Nature Publishing Group UK 2018-02-05 /pmc/articles/PMC5799179/ /pubmed/29402900 http://dx.doi.org/10.1038/s41598-018-19658-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Shiba, Kumiko Tsuchiya, Kyoichiro Komiya, Chikara Miyachi, Yasutaka Mori, Kentaro Shimazu, Noriko Yamaguchi, Shinobu Ogasawara, Naomi Katoh, Makoto Itoh, Michiko Suganami, Takayoshi Ogawa, Yoshihiro Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH |
title | Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH |
title_full | Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH |
title_fullStr | Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH |
title_full_unstemmed | Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH |
title_short | Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH |
title_sort | canagliflozin, an sglt2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human nash |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799179/ https://www.ncbi.nlm.nih.gov/pubmed/29402900 http://dx.doi.org/10.1038/s41598-018-19658-7 |
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