An increased level of plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular diseases, and PAI-1 gene expression is under the control of molecular circadian clocks in mammals. We recently showed that PAI-1 expression is augmented in a phase-advanced circadian manner in mice fed with a ketogenic diet (KD). To determine whether peroxisome proliferator-activated receptor alpha (PPAR alpha) is involved in hypofibrinolytic status induced by a MD, we examined the expression profiles of PAI-1 and circadian clock genes in PPAR alpha-null MD mice. Chronic administration of bezafibrate induced the PAI-1 gene expression in a PPAR alpha-dependent manner. Feeding with a KD augmented the circadian expression of PAI-1 mRNA in the hearts and livers of wild-type (WT) mice as previously described. The MD-induced mRNA expression of typical PPAR alpha target genes such as Cyp4A10 and FGF21 was damped in PPAR alpha-null mice. However, plasma PAI-1 concentrations were significantly more elevated in PPAR alpha-null KD mice in accordance with hepatic mRNA levels. These observations suggest that PPAR alpha activation is dispensable for MD-induced PAI-1 expression. We also found that hyperlipidemia, fatty liver, and the hepatic expressions of PPAR gamma and its coactivator PCG-1 alpha were more effectively induced in PPAR alpha-null, than in WT mice on a MD. Furthermore, KD-induced hepatic PAI-1 expression was significantly suppressed by supplementation with bisphenol A diglycidyl ether, a PPAR gamma antagonist, in both WT and PPAR alpha-null mice. PPAR gamma activation seems to be involved in MD-induced hypofibrinolysis by augmenting PAI-1 gene expression in the fatty liver. (C) 2010 Elsevier Inc. All rights reserved.