IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner
| Autor: | Wataru Ogawa, Michiko Takahashi, Yutaka Takahashi, Hitoshi Nishizawa, Ken-ichi Yoshida, Yukiko Odake, Hidenori Fukuoka, Genzo Iguchi, Ryusaku Matsumoto, Hironori Bando, Kentaro Suda |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Liver Cirrhosis
Male 0301 basic medicine Senescence medicine.medical_specialty Cirrhosis Inflammation Biology medicine.disease_cause Article Mice 03 medical and health sciences 0302 clinical medicine Non-alcoholic Fatty Liver Disease Fibrosis Internal medicine Hepatic Stellate Cells medicine Animals Insulin-Like Growth Factor I Cellular Senescence Mice Inbred ICR Multidisciplinary medicine.disease Disease Models Animal 030104 developmental biology Endocrinology Gene Expression Regulation 030220 oncology & carcinogenesis Cancer research Hepatic stellate cell Tumor Suppressor Protein p53 medicine.symptom Steatosis Hepatic fibrosis Oxidative stress |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and cirrhosis determines patient prognosis; however, effective treatment for fibrosis has not been established. Oxidative stress and inflammation activate hepatic stellate cells (HSCs) and promote fibrosis. In contrast, cellular senescence inhibits HSCs’ activity and limits fibrosis. The aim of this study was to explore the effect of IGF-I on NASH and cirrhotic models and to clarify the underlying mechanisms. We demonstrate that IGF-I significantly ameliorated steatosis, inflammation, and fibrosis in a NASH model, methionine-choline-deficient diet-fed db/db mice and ameliorated fibrosis in cirrhotic model, dimethylnitrosamine-treated mice. As the underlying mechanisms, IGF-I improved oxidative stress and mitochondrial function in the liver. In addition, IGF-I receptor was strongly expressed in HSCs and IGF-I induced cellular senescence in HSCs in vitro and in vivo. Furthermore, in mice lacking the key senescence regulator p53, IGF-I did not induce cellular senescence in HSCs or show any effects on fibrosis. Taken together, these results indicate that IGF-I induces senescence of HSCs, inactivates these cells and limits fibrosis in a p53-dependent manner and that IGF-I may be applied to treat NASH and cirrhosis. |
| Databáze: | OpenAIRE |
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