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A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis
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 apopt...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BlackWell Publishing Ltd
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154133/ https://www.ncbi.nlm.nih.gov/pubmed/24963148 http://dx.doi.org/10.15252/emmm.201403856 |
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author | 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 |
author_facet | 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 |
author_sort | Gautheron, Jérémie |
collection | PubMed |
description | 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. Subject Categories Digestive System; Metabolism |
format | Online Article Text |
id | pubmed-4154133 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BlackWell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-41541332014-09-04 A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis 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 EMBO Mol Med Research Articles 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. Subject Categories Digestive System; Metabolism BlackWell Publishing Ltd 2014-08 2014-06-24 /pmc/articles/PMC4154133/ /pubmed/24963148 http://dx.doi.org/10.15252/emmm.201403856 Text en © 2014 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles 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 A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis |
title | A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis |
title_full | A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis |
title_fullStr | A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis |
title_full_unstemmed | A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis |
title_short | A positive feedback loop between RIP3 and JNK controls non-alcoholic steatohepatitis |
title_sort | positive feedback loop between rip3 and jnk controls non-alcoholic steatohepatitis |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154133/ https://www.ncbi.nlm.nih.gov/pubmed/24963148 http://dx.doi.org/10.15252/emmm.201403856 |
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