Loss of PDK4 switches the hepatic NF-?B/TNF pathway from pro-survival to pro-apoptosis.

ABSTRACT: It has been established that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) members promote survival by upregulating antiapoptotic genes and that genetic and pharmacological inhibition of NF-?B 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-?B targets. Conclusion: PDK4 is indispensable to dictate the fate of TNF/NF-?B-mediated hepatocyte apoptosis. (Hepatology 2018).

SUBMITTER: Wu J 

PROVIDER: S-EPMC6165716 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature