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Wolf, M.J.* ; Adili, A. ; Piotrowitz, K.* ; Abdullah, Z.* ; Boege, Y.* ; Stemmer, K. ; Ringelhan, M. ; Simonavicius, N. ; Egger, M.* ; Wohlleber, D.* ; Lorentzen, A.R. ; Einer, C. ; Schulz, S. ; Clavel, T.* ; Protzer, U. ; Thiele, C.* ; Zischka, H. ; Moch, H.* ; Tschöp, M.H. ; Tumanov, A.V.* ; Haller, D.* ; Unger, K. ; Karin, M.* ; Kopf, M.* ; Knolle, P.* ; Weber, A.* ; Heikenwälder, M.

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

Cancer Cell 26, 549-564 (2014)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Hepatocellular-carcinoma; Lymphotoxin-beta; Obesity; Disease; Choline; Hepatocarcinogenesis; Nafld; Tumorigenesis; Inflammation; Progression
ISSN (print) / ISBN 1535-6108
e-ISSN 1878-3686
Journal Cancer Cell
Quellenangaben Volume: 26, Issue: 4, Pages: 549-564 Article Number: , Supplement: ,
Publisher Cell Press
Publishing Place Cambridge, Mass.
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
Institute of Diabetes and Obesity (IDO)
Institute of Molecular Toxicology and Pharmacology (TOX)
Translational Metabolic Oncology (IDC-TMO)