title: PPARα agonist fenofibrate attenuates TNF-α-induced CD40 expression in 3T3-L1 adipocytes via the SIRT1-dependent signaling pathway.
abstract: The ligand-activated transcription factor peroxisome proliferator-activated receptor-α (PPARα) 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 PPARα in inflammation is mediated by SIRT1 remains unclear. In this study, we aimed to determine the effect of PPARα agonist fenofibrate on the expressions of SIRT1 and pro-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-α (TNF-α)-stimulated adipocytes, and these effects of fenofibrate were reversed by PPARα antagonist GW6471. Moreover, SIRT1 inhibitors sirtinol/nicotinamide (NAM) or knockdown of SIRT1 could attenuate the effect of fenofibrate on TNF-α-induced CD40 expression in adipocytes. Importantly, NF-κB 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-κB p65 (Ac-NF-κB p65) in TNF-α-stimulated adipocytes, and the effect of fenofibrate was abolished by SIRT1 inhibition. In addition, fenofibrate up-regulated SIRT1 expression through AMPK in TNF-α-stimulated adipocytes. Taken together, these findings indicate that PPARα agonist fenofibrate inhibits TNF-α-induced CD40 expression in 3T3-L1 adipocytes via the SIRT1-dependent signaling pathway.
authors.affiliation: Department of Pharmacology, Cardiovascular Research Center, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors.forename: Weirong
authors.initials: W
authors.lastname: Wang
authors.forename: Qinqin
authors.initials: Q
authors.lastname: Lin
authors.forename: Rong
authors.initials: R
authors.lastname: Lin
authors.forename: Jiye
authors.initials: J
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Ren
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhang
authors.forename: Meixi
authors.initials: M
authors.lastname: Ji
authors.forename: Yanxiang
authors.initials: Y
authors.lastname: Li
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D011345:Fenofibrate / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009284:Naphthols / Q000494:pharmacology; D009536:Niacinamide / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists / Q000037:antagonists & inhibitors; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013859:Thiocarbamates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D001549:Benzamides; D019013:CD40 Antigens; C449302:GW 6471; D016328:NF-kappa B; D009284:Naphthols; D010080:Oxazoles; D047493:PPAR alpha; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C439060:sirtinol; C020972:pyrrolidine dithiocarbamic acid; D009536:Niacinamide; D014443:Tyrosine; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D011345:Fenofibrate