Antifibrotic effect of pirfenidone in a mouse model of human nonalcoholic steatohepatitis
| Autor: | Kentaro Mori, Yasutaka Miyachi, Kyoichiro Tsuchiya, Miyako Tanaka, Kozue Ochi, Shunsaku Furuke, Kazuhiko Nakabayashi, Noriko Shimazu, Kenji Ikeda, Takayoshi Suganami, Chikara Komiya, Michiko Itoh, Yoshihiro Ogawa, Kumiko Shiba, Ken Ichiro Hata, Shinobu Yamaguchi |
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| Rok vydání: | 2017 |
| Předmět: |
Liver Cirrhosis
0301 basic medicine Pyridones Apoptosis Pharmacology Article 03 medical and health sciences Idiopathic pulmonary fibrosis Non-alcoholic Fatty Liver Disease Fibrosis medicine Animals Humans Cells Cultured Inflammation Mice Knockout Liver injury Caspase 8 Multidisciplinary Caspase 3 Tumor Necrosis Factor-alpha business.industry Feeding Behavior Pirfenidone medicine.disease Up-Regulation Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Liver Diet Western Hepatocyte Hepatocytes Receptor Melanocortin Type 4 Tumor necrosis factor alpha Steatohepatitis Steatosis business medicine.drug |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep44754 |
| Popis: | Non-alcoholic steatohepatitis (NASH) is characterized by steatosis with lobular inflammation and hepatocyte injury. Pirfenidone (PFD) is an orally bioavailable pyridone derivative that has been clinically used for the treatment of idiopathic pulmonary fibrosis. However, it remains unknown whether PFD improves liver fibrosis in a mouse model with human NASH-like phenotypes. In this study, we employed melanocortin 4 receptor-deficient (MC4R-KO) mice as a mouse model with human NASH-like phenotypes to elucidate the effect and action mechanisms of PFD on the development of NASH. PFD markedly attenuated liver fibrosis in western diet (WD)-fed MC4R-KO mice without affecting metabolic profiles or steatosis. PFD prevented liver injury and fibrosis associated with decreased apoptosis of liver cells in WD-fed MC4R-KO mice. Pretreatment of PFD inhibited the tumor necrosis factor-α (TNF-α)-induced liver injury and fibrogenic responses associated with decreased apoptosis of liver cells in wild-type mice. PFD also prevented TNF-α-induced hepatocyte apoptosis in vitro with reduced activation of caspase-8 and -3. This study provides evidence for the antifibrotic effect of PFD in a mouse model of human NASH. The data of this study highlight hepatocyte apoptosis as a potential therapeutic target, and suggest that PFD can be repositioned as an antifibrotic drug for human NASH. |
| Databáze: | OpenAIRE |
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