Dataset Information

TRAF1 is a key mediator for hepatic ischemia/reperfusion injury.

ABSTRACT: Tumor necrosis factor receptor-associated factor 1 (TRAF1), an adapter in signal transduction, is involved in immunity and in apoptotic processes in various cell types. However, little is known about its function and the molecular mechanism of its activation during liver injury. This study tested the hypothesis that TRAF1 is a mediator of cell injury after hepatic ischemia/reperfusion injury (I/R). In a mouse hepatic I/R injury model, we found that TRAF1 expression was highly induced. TRAF1 deficiency was liver protective, whereas sustained TRAF1 overexpression aggravated liver injury in response to hepatic I/R injury. Mechanistic studies demonstrated that a deficiency of TRAF1 in cultured hepatocytes led to the inhibition of NF-?B-mediated inflammatory responses, suppression of the ASK/JNK pro-death pathway and promotion of cellular regeneration capacity. In contrast, the converse occurred in hepatocyte-specific TRAF1 transgenic mice. TRAF1 activated the ASK1/JNK pathway and promoted hepatic injury. Our study demonstrates that TRAF1 is a crucial early mediator of hepatic I/R injury and suggests that TRAF1 may be a potential gene therapy target for the treatment of liver injury.

SUBMITTER: Zhang XF

PROVIDER: S-EPMC4649517 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TRAF1 is a key mediator for hepatic ischemia/reperfusion injury.

Zhang X-F XF Zhang R R Huang L L Wang P-X PX Zhang Y Y Jiang D-S DS Zhu L-H LH Tian S S Zhang X-D XD Li H H

Cell death & disease 20141016

Tumor necrosis factor receptor-associated factor 1 (TRAF1), an adapter in signal transduction, is involved in immunity and in apoptotic processes in various cell types. However, little is known about its function and the molecular mechanism of its activation during liver injury. This study tested the hypothesis that TRAF1 is a mediator of cell injury after hepatic ischemia/reperfusion injury (I/R). In a mouse hepatic I/R injury model, we found that TRAF1 expression was highly induced. TRAF1 defi ...[more]

PMID: 25321474

Similar Datasets

Project description:BACKGROUND & AIMS:Ischemia-reperfusion (I/R) is a major mechanism of liver injury following hepatic surgery or transplantation. Despite numerous reports on the role of oxidative/nitrosative stress and mitochondrial dysfunction in hepatic I/R injury, the proteins that are oxidatively modified during I/R damage are poorly characterized. This study was aimed at investigating the oxidatively modified proteins underlying the mechanism for mitochondrial dysfunction in hepatic I/R injury. We also studied the effects of a superoxide dismutase mimetic/peroxynitrite scavenger metalloporphyrin (MnTMPyP) on oxidatively modified proteins and their functions. METHODS:The oxidized and/or S-nitrosylated mitochondrial proteins from I/R-injured mouse livers with or without MnTMPyP pretreatment were labeled with biotin-N-maleimide, purified with streptavidin-agarose, and resolved by 2-dimensional gel electrophoresis. The identities of the oxidatively modified proteins were determined using mass spectrometric analysis. Liver histopathology, serum transaminase levels, nitrosative stress markers, and activities of oxidatively modified mitochondrial proteins were measured. RESULTS:Comparative 2-dimensional gel analysis revealed markedly increased numbers of oxidized and S-nitrosylated mitochondrial proteins following hepatic I/R injury. Many key mitochondrial enzymes involved in cellular defense, fat metabolism, energy supply, and chaperones were identified as being oxidatively modified proteins. Pretreatment with MnTMPyP attenuated the I/R-induced increased serum transaminase levels, histologic damage, increased inducible nitric oxide synthase expression, and S-nitrosylation and/or nitration of various key mitochondrial proteins. MnTMPyP pretreatment also restored I/R-induced suppressed activities of mitochondrial aldehyde dehydrogenase, 3-ketoacyl-CoA thiolases, and adenosine triphosphate synthase. CONCLUSIONS:These results suggest that increased nitrosative stress is critically important in promoting S-nitrosylation and nitration of various mitochondrial proteins, leading to mitochondrial dysfunction with decreased energy supply and increased hepatic injury.

Dataset Information

TRAF1 is a key mediator for hepatic ischemia/reperfusion injury.

Publications

TRAF1 is a key mediator for hepatic ischemia/reperfusion injury.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets