期刊
CANCER CELL
卷 26, 期 4, 页码 549-564出版社
CELL PRESS
DOI: 10.1016/j.ccell.2014.09.003
关键词
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资金
- Helmholtz Association
- Foundation for Experimental Biomedicine Zurich (Hofschneider Foundation)
- European Research Council (LiverCancerMech)
- Helmholtz Alliance Preclinical Comprehensive Cancer Center
- Krebsliga Schweiz (Oncosuisse)
- Promedica Stiftung
- Julius Muller Stiftung
- Kurt and Santa Herrmann Stiftung
- Crohn's and Colitis Foundation of America
- Deutsche Forschungsgemeinschaft [SFB-TR36, RU742/6-1, SFB-704, SFB-TR57]
- Excellence Cluster ImmunoSensation
- Virtual Liver Network
- [GRK482]
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 LT beta R and canonical NF-B-K signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development.
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