Metabolic Activation of Intrahepatic CD8(+) T Cells and NKT Cells Causes Nonalcoholic Steatohepatitis and Liver Cancer via Cross-Talk with Hepatocytes.

Wolf, Monika Julia, MJ; Adili, Arlind, A; Piotrowitz, Kira, K; Abdullah, Zeinab, Z; Boege, Yannick, Y; Stemmer, Kerstin, K; Ringelhan, Marc, M; Simonavicius, Nicole, N; Egger, Michèle, M; Wohlleber, Dirk, D; Lorentzen, Anna, A; Einer, Claudia, C; Schulz, Sabine, S; Clavel, Thomas, T; Protzer, Ulrike, U; Thiele, Christoph, C; Zischka, Hans, H; Moch, Holger, H; Tschöp, Matthias, M; Tumanov, Alexei V, AV; Haller, Dirk, D; Unger, Kristian, K; Karin, Michael, M; Kopf, Manfred, M; Knolle, Percy, P; Weber, Achim, A; Heikenwalder, Mathias, M     «

Wolf, Monika Julia, MJ; Adili, Arlind, A; Piotrowitz, Kira, K; Abdullah, Zeinab, Z; Boege, Yannick, Y; Stemmer, Kerstin, K; Ringelhan, Marc, M; Simonavicius, Nicole, N; Egger, Michèle, M; Wohlleber, Dirk, D; Lorentzen, Anna, A; Einer, Claudia, C; Schulz, Sabine, S; Clavel, Thomas, T; Protzer, Ulrike, U; Thiele, Christoph, C; Zischka, Hans, H; Moch, Holger, H; Tschöp, Matthias, M; Tumanov, Alexei V, AV; Haller, Dirk, D; Unger, Kristian, K; Karin, Michael, M; Kopf, Manfred, M; Knolle, Percy, P; We...     »

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?R and canonical NF-?B signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development.     «

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 patient...     »