Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
Biochem Biophys Res Commun. 2010 Oct 15;401(2):313-8. doi: 10.1016/j.bbrc.2010.09.060. Epub 2010 Sep 18.
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.
纤溶酶原激活物抑制剂-1（PAI-1）水平升高被认为是心血管疾病的危险因素，而 PAI-1 基因表达受哺乳动物分子生物钟的控制。我们最近表明，在高脂肪 ketogenic 饮食喂养的小鼠中，PAI-1 表达以相位提前的生物钟方式增强。为了确定过氧化物酶体增殖物激活受体α（PPARα）是否参与高脂肪 ketogenic 饮食引起的低纤溶状态，我们检查了 PPARα 缺失高脂肪 ketogenic 饮食小鼠中 PAI-1 和生物钟基因的表达谱。长期给予 bezafibrate 以 PPARα 依赖性方式诱导 PAI-1 基因表达。如前所述，高脂肪 ketogenic 饮食增强了 WT 小鼠心脏和肝脏中 PAI-1 mRNA 的昼夜表达。高脂肪 ketogenic 饮食诱导的 Cyp4A10 和 FGF21 等典型 PPARα 靶基因的 mRNA 表达在 PPARα 缺失小鼠中减弱。然而，与肝 mRNA 水平一致，PPARα 缺失高脂肪 ketogenic 饮食小鼠的血浆 PAI-1 浓度显着升高。这些观察结果表明，PPARα 激活对于高脂肪 ketogenic 饮食诱导的 PAI-1 表达不是必需的。我们还发现，高脂血症、脂肪肝以及 PPARγ及其共激活因子 PCG-1α的肝表达在高脂肪 ketogenic 饮食的 PPARα 缺失小鼠中比在 WT 小鼠中更有效诱导。此外，在 WT 和 PPARα 缺失小鼠中，用双酚 A 二缩水甘油醚（PPARγ 拮抗剂）补充可显着抑制高脂肪 ketogenic 饮食诱导的肝 PAI-1 表达。PPARγ 激活似乎通过增强脂肪肝中 PAI-1 基因表达参与高脂肪 ketogenic 饮食引起的低纤溶。
