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

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

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)1289-1306
Number of pages18
JournalCell
Volume175
Issue number5
DOIs
Publication statusPublished - 15 Nov 2018

Keywords

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

Cite this

Grohmann, M., Wiede, F., Dodd, G. T., Gurzov, E. N., Ooi, G. J., Butt, T., ... Tiganis, T. (2018). Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. Cell, 175(5), 1289-1306. https://doi.org/10.1016/j.cell.2018.09.053
Grohmann, Marcus ; Wiede, Florian ; Dodd, Garron T. ; Gurzov, Esteban N. ; Ooi, Geraldine J. ; Butt, Tariq ; Rasmiena, Aliki A. ; Kaur, Supreet ; Gulati, Twishi ; Goh, Pei K. ; Treloar, Aislinn E. ; Archer, Stuart ; Brown, Wendy A. ; Muller, Mathias ; Watt, Matthew J. ; Ohara, Osamu ; McLean, Catriona A. ; Tiganis, Tony. / Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. In: Cell. 2018 ; Vol. 175, No. 5. pp. 1289-1306.
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title = "Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC",
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.",
keywords = "fibrosis, hepatocellular carcinoma, non-alcoholic steatohepatitis, nonalcoholic fatty liver disease, obesity, oxidative stress, protein tyrosine phosphatase, PTPN2, STAT-1, STAT-3, T cells",
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Grohmann, M, Wiede, F, Dodd, GT, Gurzov, EN, Ooi, GJ, Butt, T, Rasmiena, AA, Kaur, S, Gulati, T, Goh, PK, Treloar, AE, Archer, S, Brown, WA, Muller, M, Watt, MJ, Ohara, O, McLean, CA & Tiganis, T 2018, 'Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC' Cell, vol. 175, no. 5, pp. 1289-1306. https://doi.org/10.1016/j.cell.2018.09.053

Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. / Grohmann, Marcus; Wiede, Florian; Dodd, Garron T.; Gurzov, Esteban N.; Ooi, Geraldine J.; Butt, Tariq; Rasmiena, Aliki A.; Kaur, Supreet; Gulati, Twishi; Goh, Pei K.; Treloar, Aislinn E.; Archer, Stuart; Brown, Wendy A.; Muller, Mathias; Watt, Matthew J.; Ohara, Osamu; McLean, Catriona A.; Tiganis, Tony.

In: Cell, Vol. 175, No. 5, 15.11.2018, p. 1289-1306.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC

AU - Grohmann, Marcus

AU - Wiede, Florian

AU - Dodd, Garron T.

AU - Gurzov, Esteban N.

AU - Ooi, Geraldine J.

AU - Butt, Tariq

AU - Rasmiena, Aliki A.

AU - Kaur, Supreet

AU - Gulati, Twishi

AU - Goh, Pei K.

AU - Treloar, Aislinn E.

AU - Archer, Stuart

AU - Brown, Wendy A.

AU - Muller, Mathias

AU - Watt, Matthew J.

AU - Ohara, Osamu

AU - McLean, Catriona A.

AU - Tiganis, Tony

PY - 2018/11/15

Y1 - 2018/11/15

N2 - 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.

AB - 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.

KW - fibrosis

KW - hepatocellular carcinoma

KW - non-alcoholic steatohepatitis

KW - nonalcoholic fatty liver disease

KW - obesity

KW - oxidative stress

KW - protein tyrosine phosphatase

KW - PTPN2

KW - STAT-1

KW - STAT-3

KW - T cells

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DO - 10.1016/j.cell.2018.09.053

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JO - Cell

JF - Cell

SN - 0092-8674

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Grohmann M, Wiede F, Dodd GT, Gurzov EN, Ooi GJ, Butt T et al. Obesity Drives STAT-1-Dependent NASH and STAT-3-Dependent HCC. Cell. 2018 Nov 15;175(5):1289-1306. https://doi.org/10.1016/j.cell.2018.09.053