The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis–associated liver tumors in a novel murine model
Background: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic d...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-08-01
|
| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332221005205 |
| id |
doaj-02d4b3437efc4482872c321aa51cf391 |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Naoki Yoshioka Miyako Tanaka Kozue Ochi Akiko Watanabe Kenji Ono Makoto Sawada Tomoo Ogi Michiko Itoh Ayaka Ito Yukihiro Shiraki Atsushi Enomoto Masatoshi Ishigami Mitsuhiro Fujishiro Yoshihiro Ogawa Takayoshi Suganami |
| spellingShingle |
Naoki Yoshioka Miyako Tanaka Kozue Ochi Akiko Watanabe Kenji Ono Makoto Sawada Tomoo Ogi Michiko Itoh Ayaka Ito Yukihiro Shiraki Atsushi Enomoto Masatoshi Ishigami Mitsuhiro Fujishiro Yoshihiro Ogawa Takayoshi Suganami The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis–associated liver tumors in a novel murine model Biomedicine & Pharmacotherapy Diabetes Nonalcoholic steatohepatitis Hepatocellular carcinoma Animal model Sodium glucose cotransporter 2 inhibitor Cellular senescence |
| author_facet |
Naoki Yoshioka Miyako Tanaka Kozue Ochi Akiko Watanabe Kenji Ono Makoto Sawada Tomoo Ogi Michiko Itoh Ayaka Ito Yukihiro Shiraki Atsushi Enomoto Masatoshi Ishigami Mitsuhiro Fujishiro Yoshihiro Ogawa Takayoshi Suganami |
| author_sort |
Naoki Yoshioka |
| title |
The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis–associated liver tumors in a novel murine model |
| title_short |
The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis–associated liver tumors in a novel murine model |
| title_full |
The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis–associated liver tumors in a novel murine model |
| title_fullStr |
The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis–associated liver tumors in a novel murine model |
| title_full_unstemmed |
The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis–associated liver tumors in a novel murine model |
| title_sort |
sodium-glucose cotransporter-2 inhibitor tofogliflozin prevents the progression of nonalcoholic steatohepatitis–associated liver tumors in a novel murine model |
| publisher |
Elsevier |
| series |
Biomedicine & Pharmacotherapy |
| issn |
0753-3322 |
| publishDate |
2021-08-01 |
| description |
Background: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. Methods: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. Findings: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. Interpretation: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC. |
| topic |
Diabetes Nonalcoholic steatohepatitis Hepatocellular carcinoma Animal model Sodium glucose cotransporter 2 inhibitor Cellular senescence |
| url |
http://www.sciencedirect.com/science/article/pii/S0753332221005205 |
| work_keys_str_mv |
AT naokiyoshioka thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT miyakotanaka thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT kozueochi thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT akikowatanabe thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT kenjiono thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT makotosawada thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT tomooogi thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT michikoitoh thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT ayakaito thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT yukihiroshiraki thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT atsushienomoto thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT masatoshiishigami thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT mitsuhirofujishiro thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT yoshihiroogawa thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT takayoshisuganami thesodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT naokiyoshioka sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT miyakotanaka sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT kozueochi sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT akikowatanabe sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT kenjiono sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT makotosawada sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT tomooogi sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT michikoitoh sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT ayakaito sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT yukihiroshiraki sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT atsushienomoto sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT masatoshiishigami sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT mitsuhirofujishiro sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT yoshihiroogawa sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel AT takayoshisuganami sodiumglucosecotransporter2inhibitortofogliflozinpreventstheprogressionofnonalcoholicsteatohepatitisassociatedlivertumorsinanovelmurinemodel |
| _version_ |
1721371946996727808 |
| spelling |
doaj-02d4b3437efc4482872c321aa51cf3912021-06-19T04:52:08ZengElsevierBiomedicine & Pharmacotherapy0753-33222021-08-01140111738The sodium-glucose cotransporter-2 inhibitor Tofogliflozin prevents the progression of nonalcoholic steatohepatitis–associated liver tumors in a novel murine modelNaoki Yoshioka0Miyako Tanaka1Kozue Ochi2Akiko Watanabe3Kenji Ono4Makoto Sawada5Tomoo Ogi6Michiko Itoh7Ayaka Ito8Yukihiro Shiraki9Atsushi Enomoto10Masatoshi Ishigami11Mitsuhiro Fujishiro12Yoshihiro Ogawa13Takayoshi Suganami14Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan; Corresponding authors at: Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, JapanDepartment of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, JapanDepartment of Brain Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Molecular Pharmacokinetics, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Brain Function, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Molecular Pharmacokinetics, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Human Genetics and Molecular Biology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Kanagawa Institute of Industrial Science and Technology, Ebina, JapanDepartment of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Pathology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Pathology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, JapanDepartment of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, JapanDepartment of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan; Department of Immunometabolism, Nagoya University Graduate School of Medicine, Nagoya, Japan; Corresponding authors at: Department of Molecular Medicine and Metabolism, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.Background: Diabetes and obesity contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). However, how diabetes and obesity accelerate liver tumorigenesis remains to be fully understood. Moreover, to verify the therapeutic potential of anti-diabetic drugs, there exists a strong need for appropriate animal models that recapitulate human pathophysiology of NASH and HCC. Methods: We established a novel murine model of NASH-associated liver tumors using genetically obese melanocortin 4 receptor-deficient mice fed on Western diet in combination with a chemical procarcinogen, and verified the validity of our model in evaluating drug efficacy. Findings: Our model developed multiple liver tumors together with obesity, diabetes, and NASH within a relatively short period (approximately 3 months). In this model, sodium glucose cotransporter 2 inhibitor Tofogliflozin prevented the development of NASH-like liver phenotypes and the progression of liver tumors. Tofogliflozin attenuated p21 expression of hepatocytes in non-tumorous lesions in the liver. Interpretation: Tofogliflozin treatment attenuates cellular senescence of hepatocytes under obese and diabetic conditions. This study provides a unique animal model of NASH-associated liver tumors, which is applicable for assessing drug efficacy to prevent or treat NASH-associated HCC.http://www.sciencedirect.com/science/article/pii/S0753332221005205DiabetesNonalcoholic steatohepatitisHepatocellular carcinomaAnimal modelSodium glucose cotransporter 2 inhibitorCellular senescence |