Session: OR01-Cell Specific GH & IGF-1 Signaling
Room 134 (Moscone Center)
Nonalcoholic steatohepatitis (NASH) is a serious liver disease because it progresses to cirrhosis and the prevention of fibrosis is crucial for the treatment. An aberrant activation of hepatic stellate cells (HSCs) plays a key role in the progression of fibrosis and it has been reported that an induction of cellular senescence inactivates HSCs and suppresses fibrosis (Cell 2008, 134, 657). Recently we have reported that nonalcoholic fatty liver disease (NAFLD)/NASH are frequently associated with adult GH deficiency (AGHD) and GH replacement therapy ameliorates these conditions (EJE 2012, 167, 67, Gastroenterology 2007, 132, 938). In addition, GH deficient rat exhibited NASH, GH or IGF-I restores these changes (GH & IGF-I Res 2012, 22, 64). These results indicate that GH/IGF-I play important roles in liver and may have a potential therapeutic application for NASH. The aim of this study was to apply GH or IGF-I for a treatment of general NASH and to clarify the underlying molecular mechanisms.
Methionine-choline-deficient diet-fed db/db (MCD db/db) mouse is one of established animal models for general NASH. We examined metabolic and histological effects of GH or IGF-I administration on MCD db/db mice and analyzed oxidative stress, mitochondrial function, and activation status of HSCs. We further investigated the involvement of cellular senescence in the effect of IGF-I using p53-null (p53KO) mice.
IGF-I reduced visceral adiposity and improved insulin sensitivity in MCD db/db mice. Histologically, IGF-I, rather than GH, significantly ameliorated steatosis and fibrosis in the liver. In a mechanistic insight, IGF-I treatment restored mitochondrial function in hepatocytes concomitant with a reduced oxidative stress. In addition, we found that IGF-I receptor was strongly expressed in HSCs, and IGF-I induced cellular senescence and inhibited the activation of HSCs in vitro and vivo, suggesting that IGF-I prevents fibrosis via modulating HSCs function by inducing the cellular senescence. Convincingly, in MCD-fed p53KO mice, in which cellular senescence was impaired, IGF-I did not show any effect on the prevention of fibrosis.
The present data demonstrate that IGF-I plays a central role in the liver and prevents the progression of NASH by multiple underlying mechanisms. In particular, IGF-I decreases oxidative stress and improves mitochondrial function. Further, IGF-I directly regulates HSCs function via inducing the cellular senescence in a p53-dependent manner. These results reveal a novel mechanism of IGF-I action and suggest a potential therapeutic application for the treatment of general NASH.
Nothing to Disclose: HN, GI, HF, MT, MY, KS, HB, YT
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