Zeitschriftenaufsatz | 2018 Open Access

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

Autor:in

Grohmann, M; Wiede, Florian; Dodd, Garron; Gurzov, Esteban N.; Ooi, Geraldine; Butt, Tariq M.; Rasmiena, A.; Kaur, Supreet; Gulati, Twishi; Goh, Pei K.; Treloar, Aislinn; Archer, Stuart; Brown, Wendy; Mueller, Mathias; Watt, Matthew; Ohara, Osamu; McLean, Catriona; Tiganis, Tony

Publikationen als Autor:in / Herausgeber:in der Vetmeduni

Müller, Mathias

Journal

Cell

Abstrakt

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 C57BU 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 HASH and fibrosis. Our studies reveal how obisity-associated hepatic oxidative stress can independently contribute to the pathogenesis of NASH, fibrosis, and HCC.

Schlagwörter

Animals; CD8-Positive T-Lymphocytesimmunologymetabolism; Carcinoma, Hepatocellularmetabolismpathology; Diet, High-Fat; Disease Models, Animal; Hepatocytesmetabolism; Humans; Livermetabolismpathology; Liver Cirrhosismetabolismpathology; Liver Neoplasmsmetabolismpathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Diseasemetabolismpathology; Obesitymetabolismpathology; Oxidative Stress; Protein Tyrosine Phosphatase, Non-Receptor Type 2deficiencygeneticsmetabolism; STAT1 Transcription Factormetabolism; STAT3 Transcription Factormetabolism; Signal Transduction

Dokumententyp

Originalarbeit

CC Lizenz

CCBYNCND

Open Access Type

Hybrid

ISSN/eISSN

0092-8674 - 1097-4172

DOI

10.1016/j.cell.2018.09.053