title: A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis.
abstract: 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 RIP3-dependent "necroptosis" in NASH and NASH-induced fibrosis is currently unknown. We show that RIP3 is upregulated in human NASH and in a dietary mouse model of steatohepatitis. RIP3 mediates liver injury, inflammation, induction of hepatic progenitor cells/activated cholangiocytes, and liver fibrosis through a pathway suppressed by Caspase-8. This function of RIP3 is mediated by a positive feedback loop involving activation of Jun-(N)-terminal Kinase (JNK). Furthermore, RIP3-dependent JNK activation promotes the release of pro-inflammatory mediators like MCP-1, thereby attracting macrophages to the injured liver and further augmenting RIP3-dependent signaling, cell death, and liver fibrosis. Thus, RIP3-dependent necroptosis controls NASH-induced liver fibrosis. This pathway might represent a novel and specific target for pharmacological strategies in patients with NASH.
authors: Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), University Hospital RWTH Aachen, Aachen, Germany Interdisciplinary Centre for Clinical Research Aachen, University Hospital RWTH Aachen, Aachen, Germany.
authors: Jérémie
authors: J
authors: Gautheron
authors: Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), University Hospital RWTH Aachen, Aachen, Germany.
authors: Mihael
authors: M
authors: Vucur
authors: Institute of Virology, Technische Universität München and Helmholtz Zentrum München für Gesundheit und Umwelt (HMGU), Munich, Germany.
authors: Florian
authors: F
authors: Reisinger
authors: Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), University Hospital RWTH Aachen, Aachen, Germany.
authors: David Vargas
authors: DV
authors: Cardenas
authors: Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), University Hospital RWTH Aachen, Aachen, Germany.
authors: Christoph
authors: C
authors: Roderburg
authors: Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), University Hospital RWTH Aachen, Aachen, Germany.
authors: Christiane
authors: C
authors: Koppe
authors: Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), University Hospital RWTH Aachen, Aachen, Germany.
authors: Karina
authors: K
authors: Kreggenwinkel
authors: Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), University Hospital RWTH Aachen, Aachen, Germany.
authors: Anne Theres
authors: AT
authors: Schneider
authors: Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), University Hospital RWTH Aachen, Aachen, Germany.
authors: Matthias
authors: M
authors: Bartneck
authors: Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany.
authors: Ulf Peter
authors: UP
authors: Neumann
authors: Department of Gastroenterology and Hepatology, University Hospital University Duisburg-Essen, Essen, Germany.
authors: Ali
authors: A
authors: Canbay
authors: The Liver Group, Department of Medicine, Freeman Hospital Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK.
authors: Helen Louise
authors: HL
authors: Reeves
authors: Department of Cardiology and Angiology, University Hospital Kiel, Kiel, Germany.
authors: Mark
authors: M
authors: Luedde
authors: Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), University Hospital RWTH Aachen, Aachen, Germany.
authors: Frank
authors: F
authors: Tacke
authors: Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), University Hospital RWTH Aachen, Aachen, Germany.
authors: Christian
authors: C
authors: Trautwein
authors: Institute of Virology, Technische Universität München and Helmholtz Zentrum München für Gesundheit und Umwelt (HMGU), Munich, Germany.
authors: Mathias
authors: M
authors: Heikenwalder
authors: Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), University Hospital RWTH Aachen, Aachen, Germany tluedde@ukaachen.de.
authors: Tom
authors: T
authors: Luedde
mesh_terms: D000818:Animals; D018932:Chemokine CCL2; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D048670:MAP Kinase Kinase 4
keywords: Caspase‐8; MCP‐1; biliary ductular reaction; liver fibrosis; necroptosis