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

MJ Wolf, A Adili, K Piotrowitz, Z Abdullah, Y Boege… - Cancer cell, 2014 - cell.com
MJ Wolf, A Adili, K Piotrowitz, Z Abdullah, Y Boege, K Stemmer, M Ringelhan…
Cancer cell, 2014cell.com
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 …
Summary
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.
cell.com