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Clarification of a novel physiological function of menaquinone-4 (vitamin K2), a postulated active form of vitamin K in various tissues

澄清 Menaquinone-4（维生素 K2）的新生理功能，这是维生素 K 在多种组织中的一种假定活性形式

基本信息

批准号：
13660115
负责人：
KOMAI Michio
金额：
$ 2.24万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

Phylloquinone (vitamin K1=VK1) and the menaquinones (MK-n, or vitamin K2=VK2) are naturally occurring forms of vitamin K. Most of the menaquinones are synthesized by micro-organisms, but we have reported that MK-4 is usual in being synthesized by the conversion of orally ingested VK1 or menadione (=VK3) in the major tissues of germfree rats and mice which lack their intestinal microflora. This result denies Martius' theory that described the participation of bacterial enzyme of the intestinal flora to this conversion. Recently MK-4 has been attracted the attention of researchers due to its specific physiological action such as apoptotic activity on osteoclast cells and leukemia cells, etc. that is beneficial for the maintainance of our healthy quality of life. Therefore, we considered that MK-4 may have a specific novel function in various tissues of animals besides of coagulation in the liver and Gla-protein related action in the other tissues which all analogues of vitamin Ks have.In … More order to elucidate this hypothesis, we tried to identify genes of which expression is up-or down-regulated under VK deficient condition. DNA microarray technique is a very powerful tool to see the pofile of gene expression simultaneously. Two groups of germfree rats fed VK deficient or VK1 supplemented diet for eight days were sacrificed, and blood and tissue samples were deprived. The results of blood coagulation time (prothrombin time and activated-partial thromboplastin time) and the measurement of VK levels in various tissues supported that rats fed deficient diet showed much more sevefe VK deficient symptoms.The profile of gene expression in the liver, brain, and testis showed that the expression of diverse genes was affected under vitamin K deficiency. The series of genes which were markedly up-regulated in VK deficient liver belonged to a particular group of protein, i.e., acute phase proteins. This result was consistent with our previoous observations that VK deficient germfree mice had acute histological changes in the liver and muscle. Dietary VK1 has an anti-inflammatory effect in the LPS (lipopolysaccharide)-stimulated system in vivo, probably through its conversion to MK-4, because we observed that LPS-stimulated IL-6 expression in the primary cultured spleen was significantly inhibited by the addition of MK-4 to the culture medium rather than VK1. In conclusion, any kind of dietary VK that is considered to convert to MK-4 in various tissues has an anti-inflammatory role in the rodents and probably in humans, though detailed mechanisms involved in the effect of MK-4 should be clarified further. Less

叶绿醌（维生素K1= VK 1）和甲基萘醌（MK-n，或维生素K2= VK 2）是维生素K的天然存在形式。大多数甲基萘醌是由微生物合成的，但我们已经报道，MK-4通常是由口服摄入的VK 1或甲萘醌（= VK 3）在缺乏肠道微生物菌群的无菌大鼠和小鼠的主要组织中转化而合成的。这一结果否定了Martius的理论，该理论描述了肠道植物群的细菌酶参与这种转化。近年来，MK-4因其对破骨细胞、白血病细胞等的凋亡活性等特异性生理作用而受到研究者的关注，这些作用有利于提高我们的健康生活质量。因此，我们认为MK-4除了在肝脏中具有凝血作用和在其它组织中具有与Gla-蛋白相关的作用之外，还可能在动物的各种组织中具有特定的新功能，这是所有维生素K类似物所具有的。 ...更多信息为了阐明这一假设，我们试图鉴定在VK缺陷条件下表达上调或下调的基因。DNA微阵列技术是一种同时观察基因表达谱的有力工具。将两组无菌大鼠喂食VK缺乏或VK 1补充饮食8天后处死，并剥夺血液和组织样品。凝血时间（凝血酶原时间和活化部分凝血活酶时间）和各组织中VK水平的测定结果支持缺乏饮食的大鼠表现出更明显的VK缺乏症状。肝脏、脑和睾丸中基因表达谱显示，在维生素K缺乏时，多种基因的表达受到影响。在VK缺乏的肝脏中显著上调的一系列基因属于一组特定的蛋白质，即，急性时相蛋白这一结果与我们先前的观察一致，即VK缺陷型无菌小鼠在肝脏和肌肉中具有急性组织学变化。膳食VK 1在体内LPS（脂多糖）刺激的系统中具有抗炎作用，可能是通过其转化为MK-4，因为我们观察到，LPS刺激的IL-6在原代培养的脾中的表达被添加MK-4而不是VK 1显著抑制。总之，任何一种被认为在各种组织中转化为MK-4的饮食VK在啮齿动物中具有抗炎作用，可能在人类中也具有抗炎作用，但MK-4作用的详细机制还有待进一步阐明。少