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Gautheron, J.* ; Vucur, M.* ; Reisinger, F. ; Cardenas, D.V.* ; Roderburg, C.* ; Koppe, C.* ; Kreggenwinkel, K.* ; Schneider, A.T.* ; Bartneck, M.* ; Neumann, U.P.* ; Canbay, A.* ; Reeves, H.L.* ; Luedde, M.* ; Tacke, F.* ; Trautwein, C.* ; Heikenwälder, M. ; Luedde, T.*

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

EMBO Mol. Med. 6, 1062-1074 (2014)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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 deathso far characterized as hepatocyte apoptosisrepresents 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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Biliary Ductular Reaction ; Caspase-8 ; Liver Fibrosis ; Mcp-1 ; Necroptosis; Fatty Liver-disease; Programmed Necrosis; Hepatocyte Apoptosis; Natural-history; Cre Recombinase; Cell-death; Tnf-alpha; In-vivo; Fibrosis; Inflammation
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 1757-4676
e-ISSN 1757-4684
Zeitschrift EMBO Molecular Medicine
Quellenangaben Band: 6, Heft: 8, Seiten: 1062-1074 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Chichester
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Virology (VIRO)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-551600-001
PubMed ID 24963148
DOI 10.15252/emmm.201403856
WOS ID WOS:000340416800007
Erfassungsdatum 2014-09-15
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