The p65 subunit of NF-κB binds to PGC-1α, linking inflammation and metabolic disturbances in cardiac cells

Nuclear factor-kappa B (NF-kappa B) is a transcription factor induced by a wide range of stimuli, including hyperglycaemia and pro-inflammatory cytokines. It is associated with cardiac hypertrophy and heart failure. It was previously reported that the NF-kappa B-mediated inhibition of proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) might explain the shift in glucose metabolism during cardiac pathological processes induced by pro-inflammatory stimuli, although the specific mechanisms remain to be elucidated. We addressed the specific mechanisms by which exposure to tumour necrosis factor-alpha (TNF-alpha) results in PGC-1 alpha down-regulation in cardiac cells and, as a consequence, in the metabolic dysregulation that underlies heart dysfunction and failure. By using coimmunoprecipitation studies, we report for the first time that the p65 subunit of NF-kappa B is constitutively bound to PGC-1 alpha in human cardiac cells and also in mouse heart, and that NF-kappa B activation by TNF-alpha exposure increases this binding. Overexpression and gene silencing analyses demonstrated that the main factor limiting the degree of this association is p65, because only the modulation of this protein modified the physical interaction. Our data show that the increased physical interaction between p65 and PGC-1 alpha after NF-kappa B activation is responsible for the reduction in PGC-1 alpha expression and subsequent dysregulation of glucose oxidation. On the basis of these data, we propose that p65 directly represses PGC-1 alpha activity in cardiac cells, thereby leading to a reduction in pyruvate dehydrogenase kinase 4 (PDK4) expression and the subsequent increase in glucose oxidation observed during the proinflammatory state.