Cell
Volume 175, Issue 5, 15 November 2018, Pages 1289-1306.e20
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Article
Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC

https://doi.org/10.1016/j.cell.2018.09.053Get rights and content
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Highlights

  • Obesity promotes hepatic STAT-1 and STAT-3 signaling

  • Obesity promotes STAT-1-dependent T cell-infiltration, NASH, and fibrosis

  • Obesity promotes NASH-independent STAT-3-dependent HCC

Summary

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.

Keywords

hepatocellular carcinoma
non-alcoholic steatohepatitis
nonalcoholic fatty liver disease
fibrosis
obesity
oxidative stress
protein tyrosine phosphatase
STAT-1
STAT-3
T cells
PTPN2

Cited by (0)

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These authors contributed equally

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Present address: Université Libre de Bruxelles (ULB), Route de Lennik, 808, 1070 Brussels, Belgium

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Present address: Department of Physiology, University of Melbourne, Melbourne, VIC 3010, Australia

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