Regulation of nuclear translocation of HDAC3 by IκBα is required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptor γ function

dInhibition of peroxisome proliferator-activated receptor gamma (PPAR gamma) function by TNF-alpha contributes to glucose and fatty acid metabolic disorders in inflammation and cancer, although the molecular mechanism is not fully understood. In this study, we demonstrate that nuclear translocation of HDAC3 is regulated by TNF-alpha, and this event is required for inhibition of transcriptional activity of PPAR gamma by TNF-alpha. HDAC3 is associated with I kappa B alpha in the cytoplasm. After I kappa B alpha degradation in response to TNF-alpha, HDAC3 is subject to nuclear translocation, leading to an increase in HDAC3 activity in the nucleus. This event leads to subcellular redistribution of HDAC3. Knock-out of I kappa B alpha, but not p65 or p50, leads to disappearance of HDAC3 in the cytoplasm, which is associated with HDAC3 enrichment in the nucleus. These data suggest that inhibition of PPAR gamma by TNF-alpha is not associated with a reduction in the DNA binding activity of PPAR gamma. Rather, these results suggest that I kappa B alpha-dependent nuclear translocation of HDAC3 is responsible for PPAR gamma inhibition by TNF-alpha.