Loss of PDK4 switches the hepatic NF‐κB/TNF pathway from pro‐survival to pro‐apoptosis

It has been established that NF-κB members promote survival by upregulating anti-apoptotic genes and that genetic and pharmacological inhibition of NF-κB is required for 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, ROS production, sustained JNK activation, and reduction of 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 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 indispensible to dictate the fate of TNF/NF-κB-mediated hepatocyte apoptosis.