Oishi Katsutaka, Uchida Daisuke, Ohkura Naoki, Doi Ryosuke, Ishida Norio, Kadota Koji, Horie Shuichi
Clock Cell Biology Research Group, Institute for Biological Resources and Functions, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8566, Japan.
Arterioscler Thromb Vasc Biol. 2009 Oct;29(10):1571-7. doi: 10.1161/ATVBAHA.109.190140. Epub 2009 Jul 23.
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.
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.
Our findings suggest that ketogenic status increases hypofibrinolytic risk by inducing abnormal circadian expression of PAI-1.
糖尿病和肥胖等代谢紊乱被认为是心血管疾病的危险因素，因为它们会使血浆纤溶酶原激活物抑制剂-1（PAI-1）水平升高。生酮饮食（KDs）已被用作肥胖和非肥胖个体的减肥方法。我们研究了喂食KD（KD小鼠）的小鼠血浆PAI-1及其在组织中的mRNA表达水平的昼夜变化，以评估其对纤溶功能的影响。
在KD饮食喂养两周后，小鼠血浆中游离脂肪酸和酮水平升高，同时伴有低血糖。KD小鼠心脏和肝脏中的血浆PAI-1浓度与mRNA表达水平一致极度升高，但肾脏中未出现这种情况。在KD小鼠中，PAI-1 mRNA的昼夜表达在心脏、肾脏和脂肪组织中分别提前了4.7、7.9和7.8小时，以及昼夜节律基因mPer2和DBP的表达也提前了，这表明尽管在周期性明暗循环下随意进食，但酮症使外周生物钟提前。调节行为活动节律的昼夜节律也提前了，并且KD小鼠的自由运行周期显著缩短。
我们的研究结果表明，生酮状态通过诱导PAI-1异常的昼夜表达增加了低纤溶风险。
