Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes.
Cancer Cell
; 26(4): 549-64, 2014 Oct 13.
Article
em En
| MEDLINE
| ID: mdl-25314080
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 LTßR and canonical NF-κB signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células Matadoras Naturais
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Linfócitos T CD8-Positivos
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Hepatócitos
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Fígado Gorduroso
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Ativação Metabólica
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Neoplasias Hepáticas
Tipo de estudo:
Etiology_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Cell
Ano de publicação:
2014
Tipo de documento:
Article