Ketogenic Diet Disrupts the Circadian Clock and Increases Hypofibrinolytic Risk by Inducing Expression of Plasminogen Activator Inhibitor-1
Ketogenic Diet Disrupts the Circadian Clock and Increases Hypofibrinolytic Risk by Inducing Expression of Plasminogen Activator Inhibitor-1
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DOI：
10.1161/atvbaha.109.190140
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发表时间：
2009-10-01
影响因子：
8.7
通讯作者：
Horie, Shuichi
中科院分区：
文献类型：
--
作者：
Oishi, Katsutaka;Uchida, Daisuke;Horie, Shuichi
代谢紊乱如糖尿病和肥胖被认为是心血管疾病的危险因素，通过增加血纤溶酶原激活物抑制剂-1（派-1）的水平。生酮饮食（KD）已被用作肥胖和非肥胖个体的减肥方法。我们研究了昼夜节律的变化，血浆派-1和其mRNA的表达水平在组织中喂养的KD（KD小鼠）的小鼠，以评估其对纤溶functions.Methods和Results-Two周的kDa增加血浆水平的游离脂肪酸和酮伴随低血糖的小鼠。血浆派-1浓度极高，在心脏和肝脏中的mRNA表达水平，但不是在KD小鼠的肾脏。派-1 mRNA的昼夜节律表达分别在心脏、肾脏和脂肪组织中提前4.7、7.9和7.8小时，KD小鼠的昼夜节律基因mPer 2和DBP也是如此，这表明尽管在周期性的光暗循环下随意进食，但酮症仍使外周生物钟提前。生物钟，调节行为活动的节奏也是阶段先进的，其自由运行期显着缩短在KD mice. Conclusions，我们的研究结果表明，生酮状态通过诱导派-1的异常昼夜表达增加低纤溶风险。（Arterioscler Thromb Vasc Biol.2009; 29：1571-1577.）
Objectives-Metabolic disorders such as diabetes and obesity are considered risk factors for cardiovascular diseases by increasing levels of blood plasminogen activator inhibitor-1 (PAI-1). Ketogenic diets (KDs) have been used as an approach to weight loss in both obese and nonobese individuals. We examined circadian changes in plasma PAI-1 and its mRNA expression levels in tissues from mice fed with a KD (KD mice), to evaluate its effects on fibrinolytic functions.Methods and Results-Two weeks on the kDa increased plasma levels of free fatty acids and ketones accompanied by hypoglycemia in mice. Plasma PAI-1 concentrations were extremely elevated in accordance with mRNA expression levels in the heart and liver, but not in the kidneys of KD mice. Circadian expression of PAI-1 mRNA was phase-advanced for 4.7, 7.9, and 7.8 hours in the heart, kidney, and adipose tissues, respectively, as well as that of circadian genes mPer2 and DBP in KD mice, suggesting that peripheral clocks were phase-advanced by ketosis despite feeding ad libitum under a periodic light-dark cycle. The circadian clock that regulates behavioral activity rhythms was also phase-advanced, and its free-running period was significantly shortened in KD mice.Conclusions-Our findings suggest that ketogenic status increases hypofibrinolytic risk by inducing abnormal circadian expression of PAI-1. (Arterioscler Thromb Vasc Biol. 2009; 29: 1571-1577.)