The peroxisome proliferator-activated receptor β/δ (PPARβ/δ) agonist GW501516 prevents TNF-α-induced NF-κB activation in human HaCaT cells by reducing p65 acetylation through AMPK and SIRT1.

Nuclear factor (NF)-κB is a ubiquitously expressed transcription factor controlling the expression of numerous genes involved in inflammation. The aim of this study was to evaluate whether activation of the peroxisome proliferator-activated receptor (PPAR) β/δ prevented TNF-α-induced NF-κB activation in human HaCaT keratinocytes and, if so, to determine the mechanism involved. The PPARβ/δ agonist GW501516 inhibited the increase caused by TNF-α in the mRNA levels of the NF-κB target genes interleukin 8 (IL-8), TNF-α and thymic stromal lymphopoietin (TSLP). Likewise, GW501516 prevented the increase in NF-κB DNA-binding activity observed in cells exposed to TNF-α. The reduction in NF-κB activity following GW501516 treatment in cells stimulated with TNF-α did not involve either increased IκBα protein levels or a reduction in the translocation of the p65 subunit of NF-κB. In contrast, GW501516 treatment decreased TNF-α-induced p65 acetylation. Acetylation of p65 is mainly regulated by p300, a transcriptional co-activator that binds to and acetylates p65. Of note, AMP kinase (AMPK) activation phosphorylates p300 and reduces its binding to p65. GW501516 increased AMPK phosphorylation and the subsequent p300 phosphorylation, leading to a marked reduction in the association between p65 and this transcriptional co-activator. In addition, treatment with the PPARβ/δ agonist increased SIRT1 protein levels. Finally, the reduction in IL-8 mRNA levels following GW501516 treatment in TNF-α-stimulated cells was abolished in the presence of the PPARβ/δ antagonist GSK0660, the AMPK inhibitor compound C and the SIRT1 inhibitor sirtinol, indicating that the effects of GW501516 on NF-κB activity were dependent on PPARβ/δ, AMPK and SIRT1, respectively.

Barroso E ，Eyre E ，Palomer X ，Vázquez-Carrera M ... -  《-》

The peroxisome proliferator-activated receptor γ agonist pioglitazone prevents NF-κB activation in cisplatin nephrotoxicity through the reduction of p65 acetylation via the AMPK-SIRT1/p300 pathway.

The thiazolidinedione pioglitazone, which is also a PPAR-γ agonist, now is widely used in patients with hypercholesterolemia and hypertriglyceridemia. NF-κB is a ubiquitously expressed transcription factor controlling the expression of numerous genes involved in inflammation. The aim of the present study was to evaluate whether the activation of PPAR-γ attenuates the cisplatin-induced NF-κB activation in cisplatin nephrotoxicity. The results showed that the PPAR-γ agonist pioglitazone decreased the expression of NF-κB p65 transcription target genes (e.g., IL-6, IL-1β, and TNF-α) and inhibited histological injury and inflammatory cells infiltration in cisplatin nephrotoxicity. The suppression of NF-κB activity following pioglitazone treatment inhibited the cisplatin-induced IκB-α degredation and NF-κB p65 subunit translocation. Translocation of the NF-κB p65 subunit depends on p65 acetylation, which primarily regulated by SIRT1 or p300. Notably, AMP kinase (AMPK) activation not only decreased the phosphorylation, activation and p65 interaction of p300 but also increased SIRT1 expression, activation and p65 binding, thus leading to a significant reduction in p65 acetylation. Interestingly, the reduction of IL-6, TNF-α and IL-1β, the inhibition of histological injury and the inflammatory cells infiltration following pioglitazone treatment in cisplatin nephrotoxicity were attenuated after treatment with the PPAR-γ antagonist GW9662. These results suggest that the PPAR-γ agonist pioglitazone prevents NF-κB activation in cisplatin nephrotoxicity through a reduction in p65 acetylation via the AMPK-SIRT1/p300 pathway.

Zhang J ，Zhang Y ，Xiao F ，Liu Y ，Wang J ，Gao H ，Rong S ，Yao Y ，Li J ，Xu G ... -  《-》

Peroxisome proliferator-activated receptor beta/delta activation inhibits hypertrophy in neonatal rat cardiomyocytes.

Planavila A ，Rodríguez-Calvo R ，Jové M ，Michalik L ，Wahli W ，Laguna JC ，Vázquez-Carrera M ... -  《CARDIOVASCULAR RESEARCH》

TNF-α inhibits PPARβ/δ activity and SIRT1 expression through NF-κB in human adipocytes.

The mechanisms linking low-grade chronic inflammation with obesity-induced insulin resistance have only been partially elucidated. PPARβ/δ and SIRT1 might play a role in this association. In visceral adipose tissue (VAT) from obese insulin-resistant patients we observed enhanced p65 nuclear translocation and elevated expression of the pro-inflammatory cytokines TNF-α and IL-6 compared to control subjects. Inflammation was accompanied by a reduction in the levels of SIRT1 protein and an increase in PPARβ/δ mRNA levels. Stimulation of human mature SGBS adipocytes with TNF-α caused similar changes in PPARβ/δ and SIRT1 to those reported in obese patients. Unexpectedly, PPAR DNA-binding activity and the expression of PPARβ/δ-target genes was reduced following TNF-α stimulation, suggesting that the activity of this transcription factor was inhibited by cytokine treatment. Interestingly, the PPARβ/δ ligand GW501516 prevented the expression of inflammatory markers and the reduction in the expression of PPARβ/δ-target genes in adipocytes stimulated with TNF-α. Consistent with a role for NF-κB in the changes caused by TNF-α, treatment with the NF-κB inhibitor parthenolide restored PPAR DNA-binding activity, the expression of PPARβ/δ-target genes and the expression of SIRT1 and PPARβ/δ. These findings suggest that the reduction in PPARβ/δ activity and SIRT1 expression caused by TNF-α stimulation through NF-κB helps perpetuate the inflammatory process in human adipocytes.

Serrano-Marco L ，Chacón MR ，Maymó-Masip E ，Barroso E ，Salvadó L ，Wabitsch M ，Garrido-Sánchez L ，Tinahones FJ ，Palomer X ，Vendrell J ，Vázquez-Carrera M ... -  《-》

PPARbeta/delta agonist stimulates human lung carcinoma cell growth through inhibition of PTEN expression: the involvement of PI3K and NF-kappaB signals.

Han S ，Ritzenthaler JD ，Zheng Y ，Roman J ... -  《AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY》