PPARα agonist fenofibrate attenuates TNF-α-induced CD40 expression in 3T3-L1 adipocytes via the SIRT1-dependent signaling pathway

The ligand-activated transcription factor peroxisome proliferator-activated receptor-alpha (PPAR alpha) participates in the regulation of cellular inflammation. More recent studies indicated that sirtuin1 (SIRT1), a NAD(+)-dependent deacetylase, regulates the inflammatory response in adipocytes. However, whether the role of PPARa in inflammation is mediated by SIRT1 remains unclear. In this study, we aimed to determine the effect of PPAR alpha agonist fenofibrate on the expressions of SIRT1 and pip-inflammatory cytokine CD40 and underlying mechanisms in 3T3-L1 adipocytes. We found that fenofibrate inhibited CD40 expression and up-regulated SIRT1 expression in tumor necrosis factor-alpha (TNF-alpha)-stimulated adipocytes, and these effects of fenofibrate were reversed by PPARa antagonist GW6471. Moreover, SIRT1 inhibitors sirtinol/nicotinamide (NAM) or knock. down of SIRT1 could attenuate the effect of fenofibrate on TNF-alpha-induced CD40 expression in adipocytes. Importantly, NF-kappa B inhibitor pyrrolidine dithiocarbamate (PDTC) augmented the effect of fenofibrate on CD40 expression in adipocytes. Further study found that fenofibrate decreased the expression of acetylated-NF-kappa B p65 (Ac-NF-kappa B p65) in TNF-alpha-stimulated adipocytes, and the effect of fenofibrate was abolished by SIRT1 inhibition. In addition, fenofibrate upregulated SIRT1 expression through AMPK in TNF-alpha-stimulated adipocytes. Taken together, these findings indicate that PPAR alpha agonist fenofibrate inhibits TNF-alpha-induced CD40 expression in 3T3-L1 adipocytes via the SIRT1-dependent signaling pathway. (C) 2013 Elsevier Inc. All rights reserved.