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

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).