A positive feedback loop between RIP3 and JNK controls non‐alcoholic steatohepatitis

EMBO Molecular Medicine

Jérémie Gautheron¹  Mihael Vucur¹  Florian Reisinger⁶  David Vargas Cardenas¹  Christoph Roderburg¹  Christiane Koppe¹  Karina Kreggenwinkel¹  Anne Theres Schneider¹  Matthias Bartneck¹  Ulf Peter Neumann³  Ali Canbay⁴  Helen Louise Reeves⁵  Mark Luedde²  Frank Tacke¹  Christian Trautwein¹  Mathias Heikenwalder⁶ 

[1] Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine (Department of Medicine III), University Hospital RWTH Aachen, Aachen, Germany;Department of Cardiology and Angiology, University Hospital Kiel, Kiel, Germany;Department of Visceral and Transplantation Surgery, University Hospital RWTH Aachen, Aachen, Germany;Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany;The Liver Group, Department of Medicine, Freeman Hospital, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, UK;Institute of Virology, Technische Universität München and Helmholtz Zentrum München für Gesundheit und Umwelt (HMGU), Munich, Germany

关键词: biliary ductular reaction;    Caspase‐8;    liver fibrosis;    MCP‐1;    necroptosis;   

DOI  :  10.15252/emmm.201403856

来源: Wiley

【 摘 要 】

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.

Synopsis

RIP3-dependent necroptosis mediates NASH-induced liver fibrosis via activation of JNK, MCP-1-mediated recruitment of monocytes, and an expansion of intrahepatic biliary/progenitor cells. Caspase-8 appears to suppress the deleterious effect of RIP3.

• RIP3 mediates liver injury in MCD-diet-induced NASH.
• RIP3—similar to Caspase-8—does not affect CCl4-induced liver fibrosis and thus might be a specific target in metabolic liver disease.
• Human NASH livers strongly express RIP3.
• Targeting RIP3 might represent a novel-specific approach in human NASH.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.