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

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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