It was reported that glucocorticoid production was inhibited by fenofibrate through suppression of type-1 11 beta-hydroxysteroid dehydrogenase gene expression in liver. The inhibition might be a negative-feedback regulation of glucocorticoid receptor (GR) activity by peroxisome proliferator-activated receptor alpha (PPAR alpha), which is quickly induced by glucocorticoid in the liver. However, it is not clear if GR expression is changed by fenofibrate-induced PPAR alpha activation. In this study, we tested this possibility in the liver of Sprague-Dawley rats. GR expression was reduced by fenolibrate in a time- and does-dependent manner. The inhibition was observed in liver, but not in fat and muscle. The corticosterone level in the blood was increased significantly by fenofibrate. These effects of fenofibrate were abolished by PPAR alpha inhibitor MK886, suggesting that fenofibrate activated through PPAR alpha. In conclusion, inhibition of GR expression may represent a new molecular mechanism for the negative feedback regulation of GR activity by PPAR alpha. (C) 2008 Elsevier Inc. All rights reserved.