Open AccessA positive feedback loop between RIP 3 and JNK controls non‐alcoholic steatohepatitis
Author(s) -
Gautheron Jérémie,
Vucur Mihael,
Reisinger Florian,
Cardenas David Vargas,
Roderburg Christoph,
Koppe Christiane,
Kreggenwinkel Karina,
Schneider Anne Theres,
Bartneck Matthias,
Neumann Ulf Peter,
Canbay Ali,
Reeves Helen Louise,
Luedde Mark,
Tacke Frank,
Trautwein Christian,
Heikenwalder Mathias,
Luedde Tom
Publication year - 2014
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201403856
Subject(s) - steatohepatitis , necroptosis , fatty liver , fibrosis , steatosis , hepatocyte , cancer research , liver injury , alcoholic liver disease , liver disease , biology , medicine , programmed cell death , apoptosis , endocrinology , cirrhosis , disease , biochemistry , in vitro
Non‐alcoholic fatty liver disease ( NAFLD ) represents the most common liver disease in Western countries and often progresses to non‐alcoholic steatohepatitis ( NASH ) leading ultimately to liver fibrosis and liver cancer. The occurrence of hepatocyte cell death—so far characterized as hepatocyte apoptosis—represents a fundamental step from benign steatosis toward progressive steatohepatitis. In contrast, the function of RIP 3‐dependent “necroptosis” in NASH and NASH ‐induced fibrosis is currently unknown. We show that RIP 3 is upregulated in human NASH and in a dietary mouse model of steatohepatitis. RIP 3 mediates liver injury, inflammation, induction of hepatic progenitor cells/activated cholangiocytes, and liver fibrosis through a pathway suppressed by Caspase‐8. This function of RIP 3 is mediated by a positive feedback loop involving activation of Jun‐(N)‐terminal Kinase ( JNK ). Furthermore, RIP 3‐dependent JNK activation promotes the release of pro‐inflammatory mediators like MCP ‐1, thereby attracting macrophages to the injured liver and further augmenting RIP 3‐dependent signaling, cell death, and liver fibrosis. Thus, RIP 3‐dependent necroptosis controls NASH ‐induced liver fibrosis. This pathway might represent a novel and specific target for pharmacological strategies in patients with NASH .