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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)
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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
Language english
Publication Year 2014
HGF-reported in Year 2014
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)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30201 - Metabolic Health
30203 - Molecular Targets and Therapies
Research field(s) Immune Response and Infection
Helmholtz Diabetes Center
Enabling and Novel Technologies
Radiation Sciences
PSP Element(s) G-551600-001
G-502200-001
G-502700-003
G-505200-003
G-521800-001
G-501000-001
PubMed ID 25314080
DOI 10.1016/j.ccell.2014.09.003
WOS ID WOS:000343343800014
Scopus ID 84907976095
Erfassungsdatum 2014-10-16
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