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Publication : IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner.

First Author  Nishizawa H Year  2016
Journal  Sci Rep Volume  6
Pages  34605 PubMed ID  27721459
Mgi Jnum  J:346815 Mgi Id  MGI:6223338
Doi  10.1038/srep34605 Citation  Nishizawa H, et al. (2016) IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner. Sci Rep 6:34605
abstractText  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.
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