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

• DOI: 10.1016/j.ccell.2014.09.003
• Publication Date: 2014-10-13T12:01:03Z
• Authors: Monika Julia Wolf; Arlind Adili; Kira Piotrowitz; Zeinab Abdullah; Yannick Boege; Kerstin Stemmer; Marc Ringelhan; Nicole Simonavicius; Michèle Egger; Dirk Wohlleber; Anna Lorentzen; Claudia Einer; Sabine Schulz; Thomas Clavel; Ulrike Protzer; Christoph Thiele; Hans Zischka; Holger Moch; Matthias Tschöp; Alexei V. Tumanov; Dirk Haller; Kristian Unger; Michael Karin; Manfred Kopf; Percy Knolle; Achim Weber; Mathias Heikenwalder
• Keywords: Steatohepatitis; Liver Cancer

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.