Jianguo Wu1, Yulan Zhao1, Young-Ki Park2, Ji-Young Lee2, Ling Gao3,4,5, Jiajun Zhao3,4,5, Li Wang1,6,7. 1. Department of Physiology and Neurobiology, Institute for Systems Genomics, University of Connecticut, Storrs, CT. 2. Department of Nutritional Sciences, Institute for Systems Genomics, University of Connecticut, Storrs, CT. 3. Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China. 4. Shandong Clinical Medical Center of Endocrinology and Metabolism, Jinan, China. 5. Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, China. 6. Veterans Affairs Connecticut Healthcare System, West Haven, CT. 7. Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT.
Abstract
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).
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).