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

Lookup NU author(s): Professor Helen ReevesORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Gautheron J, Vucur M, Reisinger F, Cardenas DV, Roderburg C, Koppe C, Kreggenwinkel K, Schneider AT, Bartneck M, Neumann UP, Canbay A, Reeves HL, Luedde M, Tacke F, Trautwein C, Heikenwalder M, Luedde T

Publication type: Article

Publication status: Published

Journal: EMBO Molecular Medicine

Year: 2014

Volume: 6

Issue: 8

Pages: 1062-1074

Print publication date: 01/08/2014

Online publication date: 24/06/2014

Acceptance date: 22/05/2014

Date deposited: 02/10/2014

ISSN (print): 1757-4676

ISSN (electronic): 1757-4684

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.15252/emmm.201403856


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Funder referenceFunder name
ERC Starting grant (LiverCancerMechanisms)
Helmholtz Foundation
Interdisciplinary-Centre-for-Clinical-Research (IZKF)
EMBO Young Investigator Program
Helmholtz alliance preclinical comprehensive center (PCCC)
Hofschneider Foundation
medical faculty of the RWTH Aachen
12/12Deutsche Stiftung Herzforschung
ERC-2007-Stg/208237-Luedde-Med3-AachenERC Starting Grant
Deutsche Krebshilfe 110043German Cancer Aid