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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.

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.

journal_name

Cancer Cell

journal_title

Cancer cell

authors

Wolf MJ,Adili A,Piotrowitz K,Abdullah Z,Boege Y,Stemmer K,Ringelhan M,Simonavicius N,Egger M,Wohlleber D,Lorentzen A,Einer C,Schulz S,Clavel T,Protzer U,Thiele C,Zischka H,Moch H,Tschöp M,Tumanov AV,Haller D,Ung

doi

10.1016/j.ccell.2014.09.003

subject

Has Abstract

pub_date

2014-10-13 00:00:00

pages

549-64

issue

4

eissn

1535-6108

issn

1878-3686

pii

S1535-6108(14)00366-3

journal_volume

26

pub_type

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