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

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          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.

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          Author and article information

          Journal
          Cancer Cell
          Cancer cell
          1878-3686
          1535-6108
          Oct 13 2014
          : 26
          : 4
          Affiliations
          [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.
          Article
          S1535-6108(14)00366-3
          10.1016/j.ccell.2014.09.003
          25314080
          cd9b21a4-bb55-4180-a62a-45d387d2739d
          Copyright © 2014 Elsevier Inc. All rights reserved.
          History

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