PDK4型
肿瘤坏死因子α
细胞凋亡
细胞生物学
癌症研究
激酶
NF-κB
信号转导
生物
化学
下调和上调
免疫学
生物化学
基因
作者
Jiang Wu,Yulan Zhao,Youngki Park,Jiyoung Lee,Ling Gao,Jiajun Zhao,Li Wang
出处
期刊:Hepatology
[Wiley]
日期:2018-05-20
卷期号:68 (3): 1111-1124
被引量:60
摘要
It has been established that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) members promote survival by upregulating antiapoptotic genes and that genetic and pharmacological inhibition of NF-κB is required for tumor necrosis factor (TNF)-induced hepatocyte apoptosis. In this study, we demonstrate that this pro-survival pathway is switched to pro-apoptosis under pyruvate dehydrogenase kinase 4 (PDK4)-deficient conditions. PDK4-deficiency triggered hepatic apoptosis concomitantly with increased numbers of aberrant mitochondria, reactive oxygen species (ROS) production, sustained c-Jun N-terminal Kinase (JNK) activation, and reduction of glutathione (GSH). Interestingly, PDK4 retained p65 in cytoplasm via a direct protein-protein interaction. Disruption of PDK4-p65 association promoted p65 nuclear translocation. This, in turn, facilitated p65 binding to the TNF promoter to activate TNF-TNFR1 apoptotic pathway. Pdk4-/- livers were sensitized to Jo2 and D-(+)-Galactosamine /Lipopolysaccharide (GalN/LPS)-mediated apoptotic injury which was prevented by the inhibition of p65 or TNFR1. The pro-survival activity of TNF was shifted, which was switched to a pro-apoptotic activity in Pdk4-/- hepatocytes as a result of impaired activation of pro-survival NF-κB targets. Conclusion: PDK4 is indispensable to dictate the fate of TNF/NF-κB-mediated hepatocyte apoptosis. (Hepatology 2018).
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