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    Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC

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    Author
    Grohmann, M; Wiede, F; Dodd, GT; Gurzov, EN; Ooi, GJ; Butt, T; Rasmiena, AA; Kaur, S; Gulati, T; Goh, PK; ...
    Date
    2018-11-15
    Source Title
    Cell
    Publisher
    CELL PRESS
    University of Melbourne Author/s
    Tiganis, Tony; Watt, Matthew; McLean, Catriona; Gurzov, Esteban; Dodd, Garron
    Affiliation
    Florey Department of Neuroscience and Mental Health
    Sir Peter MacCallum Department of Oncology
    Medicine and Radiology
    Physiology
    Metadata
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    Document Type
    Journal Article
    Citations
    Grohmann, M., Wiede, F., Dodd, G. T., Gurzov, E. N., Ooi, G. J., Butt, T., Rasmiena, A. A., Kaur, S., Gulati, T., Goh, P. K., Treloar, A. E., Archer, S., Brown, W. A., Muller, M., Watt, M. J., Ohara, O., McLean, C. A. & Tiganis, T. (2018). Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. CELL, 175 (5), pp.1289-+. https://doi.org/10.1016/j.cell.2018.09.053.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/253280
    DOI
    10.1016/j.cell.2018.09.053
    Abstract
    Obesity is a major driver of cancer, especially hepatocellular carcinoma (HCC). The prevailing view is that non-alcoholic steatohepatitis (NASH) and fibrosis or cirrhosis are required for HCC in obesity. Here, we report that NASH and fibrosis and HCC in obesity can be dissociated. We show that the oxidative hepatic environment in obesity inactivates the STAT-1 and STAT-3 phosphatase T cell protein tyrosine phosphatase (TCPTP) and increases STAT-1 and STAT-3 signaling. TCPTP deletion in hepatocytes promoted T cell recruitment and ensuing NASH and fibrosis as well as HCC in obese C57BL/6 mice that normally do not develop NASH and fibrosis or HCC. Attenuating the enhanced STAT-1 signaling prevented T cell recruitment and NASH and fibrosis but did not prevent HCC. By contrast, correcting STAT-3 signaling prevented HCC without affecting NASH and fibrosis. TCPTP-deletion in hepatocytes also markedly accelerated HCC in mice treated with a chemical carcinogen that promotes HCC without NASH and fibrosis. Our studies reveal how obesity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC.

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