The Peroxisome Proliferator-Activated Receptor-γ Agonist Pioglitazone Represses Inflammation in a Peroxisome Proliferator-Activated Receptor-α–Dependent Manner In Vitro and In Vivo in Mice

Objectives Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone modulates inflammation through PPARα mechanisms. Background The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPARγ agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPARα but not PPARγ agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPARα activation, we studied pioglitazoneʹs effects via PPARα. Methods Pioglitazone effects on known PPARα responses—ligand binding domain activation and PPARα target gene expression—were tested in vitro and in vivo, including in wild-type and PPARα-deficient cells and mice, and compared with the effects of other PPARγ (rosiglitazone) and PPARα (WY14643) agonists. Results Pioglitazone repressed endothelial TNFα-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IκBα in a manner dependent on both pioglitazone exposure and PPARα expression. Pioglitazone also activated the PPARα ligand binding domain and induced PPARα target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IκBα expression in wild-type but not PPARα-deficient mice. Conclusions Pioglitazone regulates inflammatory target genes in hepatic (IκBα) and endothelial (VCAM-1) settings in a PPARα-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.