Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes - PubMed (original) (raw)

. 2014 Oct 13;26(4):549-64.

doi: 10.1016/j.ccell.2014.09.003.

Arlind Adili 2, Kira Piotrowitz 3, Zeinab Abdullah 4, Yannick Boege 1, Kerstin Stemmer 5, Marc Ringelhan 6, Nicole Simonavicius 2, Michèle Egger 1, Dirk Wohlleber 7, Anna Lorentzen 2, Claudia Einer 8, Sabine Schulz 8, Thomas Clavel 9, Ulrike Protzer 2, Christoph Thiele 3, Hans Zischka 8, Holger Moch 1, Matthias Tschöp 5, Alexei V Tumanov 10, Dirk Haller 11, Kristian Unger 12, Michael Karin 13, Manfred Kopf 14, Percy Knolle 15, Achim Weber 16, Mathias Heikenwalder 17

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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

Monika Julia Wolf et al. Cancer Cell. 2014.

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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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