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)-gamma agonist pioglitazone modulates inflammation through PPAR alpha mechanisms. Background The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPAR gamma 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 PPAR alpha but not PPAR alpha agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPAR alpha activation, we studied pioglitazone's effects via PPAR alpha. Methods Pioglitazone effects on known PPAR alpha responses-ligand binding domain activation and PPAR alpha target gene expression -were tested in vitro and in vivo, including in wild-type and PPAR alpha-deficient cells and mice, and compared with the effects of other PPAR alpha (rosiglitazone) and PPAR alpha (WY14643) agonists. Results Pioglitazone repressed endothelial TNF alpha-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic I kappa B alpha in a manner dependent on both pioglitazone exposure and PPAR alpha expression. Pioglitazone also activated the PPAR alpha ligand binding domain and induced PPAR alpha target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and I kappa B alpha expression in wild-type but not PPAR alpha-deficient mice. Conclusions Pioglitazone regulates inflammatory target genes in hepatic (I kappa B alpha) and endothelial (VCAM-1) settings in a PPAR alpha-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.