title: PPARα deficiency augments a ketogenic diet-induced circadian PAI-1 expression possibly through PPARγ activation in the liver.
abstract: 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 α (PPARα) is involved in hypofibrinolytic status induced by a KD, we examined the expression profiles of PAI-1 and circadian clock genes in PPARα-null KD mice. Chronic administration of bezafibrate induced the PAI-1 gene expression in a PPARα-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 KD-induced mRNA expression of typical PPARα target genes such as Cyp4A10 and FGF21 was damped in PPARα-null mice. However, plasma PAI-1 concentrations were significantly more elevated in PPARα-null KD mice in accordance with hepatic mRNA levels. These observations suggest that PPARα activation is dispensable for KD-induced PAI-1 expression. We also found that hyperlipidemia, fatty liver, and the hepatic expressions of PPARγ and its coactivator PCG-1α were more effectively induced in PPARα-null, than in WT mice on a KD. Furthermore, KD-induced hepatic PAI-1 expression was significantly suppressed by supplementation with bisphenol A diglycidyl ether, a PPARγ antagonist, in both WT and PPARα-null mice. PPARγ activation seems to be involved in KD-induced hypofibrinolysis by augmenting PAI-1 gene expression in the fatty liver.
authors.affiliation: Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan. k-ooishi@aist.go.jp
authors.forename: Katsutaka
authors.initials: K
authors.lastname: Oishi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Uchida
authors.forename: Naoki
authors.initials: N
authors.lastname: Ohkura
authors.forename: Shuichi
authors.initials: S
authors.lastname: Horie
mesh_terms: D000818:Animals; D002940:Circadian Rhythm; D004032:Diet; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism; D007659:Ketones / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics*; D047495:PPAR gamma / Q000096:biosynthesis*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*
chemical_list: D007659:Ketones; D047493:PPAR alpha; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1