Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis–associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects

Mitsuhiro Kawakubo, Miyako Tanaka, Kozue Ochi, Akiko Watanabe, Marie Saka-Tanaka, Yohei Kanamori, Naoki Yoshioka, Satoko Yamashita, Moritaka Goto, Michiko Itoh, Ibuki Shirakawa, Sayaka Kanai, Hiromi Suzuki, Makoto Sawada, Ayaka Ito, Masatoshi Ishigami, Mitsuhiro Fujishiro, Hiroshi Arima, Yoshihiro Ogawa, Takayoshi Suganami

研究成果: ジャーナルへの寄稿記事

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Nonalcoholic steatohepatitis (NASH) is a hepatic phenotype of the metabolic syndrome, and increases the risk of cirrhosis and hepatocellular carcinoma (HCC). Although increasing evidence points to the therapeutic implications of certain types of anti-diabetic agents in NASH, it remains to be elucidated whether their effects on NASH are independent of their effects on diabetes. Genetically obese melanocortin 4 receptor–deficient (MC4R-KO) mice fed Western diet are a murine model that sequentially develops hepatic steatosis, NASH, and HCC in the presence of obesity and insulin resistance. In this study, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin on NASH and HCC development in MC4R-KO mice. Anagliptin treatment effectively prevented inflammation, fibrosis, and carcinogenesis in the liver of MC4R-KO mice. Interestingly, anagliptin only marginally affected body weight, systemic glucose and lipid metabolism, and hepatic steatosis. Histological data and gene expression analysis suggest that anagliptin treatment targets macrophage activation in the liver during the progression from simple steatosis to NASH. As a molecular mechanism underlying anagliptin action, we showed that glucagon-like peptide-1 suppressed proinflammatory and profibrotic phenotypes of macrophages in vitro. This study highlights the glucose metabolism–independent effects of anagliptin on NASH and HCC development.

元の言語英語
記事番号983
ジャーナルScientific reports
10
発行部数1
DOI
出版物ステータス出版済み - 12 1 2020

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All Science Journal Classification (ASJC) codes

  • General

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