Reference - Detail
|Author||Komiya C, Tanaka M, Tsuchiya K, Shimazu N, Mori K, Furuke S, Miyachi Y, Shiba K, Yamaguchi S, Ikeda K, Ochi K, Nakabayashi K, Hata KI, Itoh M, Suganami T, Ogawa Y.|
|Title||Antifibrotic effect of pirfenidone in a mouse model of human nonalcoholic steatohepatitis.|
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.
|MeSH||Animals Apoptosis / drug effects Caspase 3 / metabolism Caspase 8 / metabolism Cells, Cultured Diet, Western Disease Models, Animal Feeding Behavior / drug effects Hepatocytes / drug effects Hepatocytes / metabolism Hepatocytes / pathology Humans Inflammation / pathology Liver / drug effects Liver / pathology Liver Cirrhosis / drug therapy Liver Cirrhosis / pathology Mice, Inbred C57BL Mice, Knockout Non-alcoholic Fatty Liver Disease / blood Non-alcoholic Fatty Liver Disease / drug therapy* Non-alcoholic Fatty Liver Disease / genetics Non-alcoholic Fatty Liver Disease / pathology Pyridones / pharmacology Pyridones / therapeutic use* Receptor, Melanocortin, Type 4 / deficiency Receptor, Melanocortin, Type 4 / metabolism Tumor Necrosis Factor-alpha / adverse effects Up-Regulation / genetics|
|WOS Category||GASTROENTEROLOGY & HEPATOLOGY|
|Human and Animal Cells||RAW 264(RCB0535)|