Likewise, both Raptor and mTOR phosphorylation were increased in obese mice,

indicative of mTORC1 activation. The functional relevance of this for control of hepatocyte growth was evident by enhanced phosphorylation of both 4E-BP1 and elF-4B, which are the key downstream targets of mTOR that control growth, protein synthesis, cell proliferation and cell survival. In order to gain further evidence for the role of mTOR signaling in tumor cell growth, Barasertib manufacturer we treated primary HCC cells derived from DEN-injected foz/foz mice with rapamycin. MTT assay revealed that rapamycin markedly decreased HCC cell viability after 48 hours treatment in dose-dependent manner vs control. Further, rapamycin reduced levels of phospho-mTOR, phospho-4E-BP1 and phospho-p70S6K protein expressions, leading to down-regulation of cyclin D1 and cyclin E. These results further support the crucial role of mTORC1 pathway in hepatocyte growth and proliferation. Conclusions: Enhanced growth of dysplastic hepatocytes in the early stages of obesity-accelerated hepatocarcinogenesis is associated with hyperinsulinemia and hyperglycemia

that induces and activates the Akt/mTOR pathway to promote hepatocyte growth in obese-diabetic mice with HCC. AS WILKINSON,1,2 KR BRIDLE,1,2 LJ BRITTON,1,2 mTOR inhibitor LA JASKOWSKI,1,2 LM FLETCHER,3 VN SUBRAMANIAM,1,4 DHG CRAWFORD1,2 1School of Medicine, The University of Queensland, 2Gallipoli Medical Research Foundation, Greenslopes Private Hospital, 3Department of Gastroenterology MCE公司 and

Hepatology, Princess Alexandra Hospital 4The Queensland Institute of Medical Research, Brisbane, Australia Introduction: Iron and/or HFE mutations have been proposed as having an important role in the progression of liver disease in subjects with non-alcoholic fatty liver disease (NAFLD). Previous work in our laboratory has shown a greater severity of injury in Hfe-/- mice fed a high calorie diet (HCD) compared with wild-type mice. We examined the contribution of iron to the development of steatosis in an animal model of haemochromatosis by feeding mice an iron-deficient diet followed by exposure to a HCD. Methods: Hfe-/- mice were fed either a control diet, HCD, iron-deficient control diet (Fe-Def control) or iron-deficient HCD (Fe-Def HCD) for 8 weeks (n = 10 per group). Livers were analysed for their hepatic iron concentration (HIC) and quantitative expression of iron metabolism genes by real-time PCR. Histological parameters were staged and graded by a specialist liver pathologist in a blinded fashion. Results: Visceral adipose tissue (VAT) and liver weights were increased in Hfe-/- mice fed HCD compared to the control diet (Figure 1A). Interestingly, mice fed the iron-deficient HCD had significantly lower liver weights compared to the mice fed HCD (Figure 1B).

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