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Cancer Cell. 2014 Oct 13;26(4):549-64. doi: 10.1016/j.ccell.2014.09.003.

Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes.

Author information

1
Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland.
2
Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich 81675, Germany.
3
LIMES Life and Medical Sciences Institute, University of Bonn, Bonn 53125, Germany.
4
Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn 53105, Germany.
5
Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München & Division of Metabolic Diseases, Technische Universität München, Munich 81657, Germany.
6
Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich 81675, Germany; Second Medical Department, Klinikum Rechts der Isar, Technische Universität München, Munich 81657, Germany.
7
Institute of Molecular Immunology, Technische Universität München, Munich 81675, Germany.
8
Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg 85764, Germany.
9
Junior Group Intestinal Microbiome, Technische Universität München, Freising-Weihenstephan 85350, Germany; Chair of Nutrition and Immunology, ZIEL-Research Center for Nutrition and Food Sciences, Biofunctionality Unit, Technische Universität München, Freising-Weihenstephan 85350, Germany.
10
Trudeau Institute, Saranac Lake, New York, NY 12983, USA.
11
Chair of Nutrition and Immunology, ZIEL-Research Center for Nutrition and Food Sciences, Biofunctionality Unit, Technische Universität München, Freising-Weihenstephan 85350, Germany.
12
Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
13
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego, School of Medicine, San Diego, CA 92093, USA.
14
Molecular Biomedicine, Institute of Molecular Health Sciences, ETH Zurich, Zurich 8093, Switzerland.
15
Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn 53105, Germany; Institute of Molecular Immunology, Technische Universität München, Munich 81675, Germany.
16
Institute of Surgical Pathology, University Hospital Zurich, Zurich 8091, Switzerland. Electronic address: achim.weber@usz.ch.
17
Institute of Virology, Technische Universität München and Helmholtz Zentrum München, Munich 81675, Germany. Electronic address: heikenwaelder@helmholtz-muenchen.de.

Abstract

Hepatocellular carcinoma (HCC), the fastest rising cancer in the United States and increasing in Europe, often occurs with nonalcoholic steatohepatitis (NASH). Mechanisms underlying NASH and NASH-induced HCC are largely unknown. We developed a mouse model recapitulating key features of human metabolic syndrome, NASH, and HCC by long-term feeding of a choline-deficient high-fat diet. This induced activated intrahepatic CD8(+) T cells, NKT cells, and inflammatory cytokines, similar to NASH patients. CD8(+) T cells and NKT cells but not myeloid cells promote NASH and HCC through interactions with hepatocytes. NKT cells primarily cause steatosis via secreted LIGHT, while CD8(+) and NKT cells cooperatively induce liver damage. Hepatocellular LTβR and canonical NF-κB signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development.

PMID:
25314080
DOI:
10.1016/j.ccell.2014.09.003
[Indexed for MEDLINE]
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