期刊
EMBO MOLECULAR MEDICINE
卷 6, 期 8, 页码 1062-1074出版社
WILEY
DOI: 10.15252/emmm.201403856
关键词
biliary ductular reaction; Caspase-8; liver fibrosis; MCP-1; necroptosis
资金
- German-Research-Foundation [SFB-TRR57/P06, SFB-TR36]
- German Cancer Aid [Deutsche Krebshilfe 110043]
- ERC Starting Grant [ERC-2007-Stg/208237-Luedde-Med3-Aachen]
- EMBO Young Investigator Program
- Ernst-Jung-Foundation/Hamburg
- Interdisciplinary-Centre-for-Clinical-Research (IZKF)
- medical faculty of the RWTH Aachen
- Helmholtz Foundation
- Hofschneider Foundation
- Helmholtz alliance preclinical comprehensive center (PCCC)
- ERC Starting grant (LiverCancerMechanisms)
- Deutsche Stiftung Herzforschung [12/12]
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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