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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

Research Project

Project/Area Number 13660115
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field 食品科学・栄養科学
Research InstitutionTohoku University

Principal Investigator

KOMAI Michio  Laboratory of Nutrition, Division of Life Science, Graduate School of Agricultural Science, Professor, 大学院・農学研究科, 教授 (80143022)

Co-Investigator(Kenkyū-buntansha) ITO Michiko  Laboratory of Nutrition, Department of Biological Chemistry, Faculty of Agriculture, Technical Official, 農学部, 技官 (60250734)
FURUKAWA Yuji  Laboratory of Nutrition, Division of Life Science, Graduate School of Agricultural Science, Professor, 大学院・農学研究科, 教授 (60005626)
SHIRAKAWA Hitoshi  Laboratory of Nutrition, Division of Life Science, Graduate School of Agricultural Science, Assistant Professor, 大学院・農学研究科, 助手 (40206280)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2001: ¥2,100,000 (Direct Cost: ¥2,100,000)
Keywordsvitamin K / menaquinone-4 / IL-6 (Interleukin-6) / anti-inflammatory effect / lipopolysaccharide (LPS) / rat liver / mouse spleen / メナキノン-4(Mk-4) / ラット / Mk-4生成酵素 / DNAマイクロアレイ
Research Abstract

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

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] 駒井三千夫, 白井仁, ほか: "DNAマイクロアレイによる栄養素の新しい作用の検索"Boundary. 17. 30-32 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 駒井三千夫, 白井仁, ほか: "無菌ビタミンK欠乏ラットを用いたビタミンK新規作用の検索"無菌生物. 31. 50-53 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 駒井三千夫, 白井仁, ほか: "メナキノン-4(ビタミンK_2)の組織内生成機構の解析"第5回Vitamin K & Bone研究記録集. 5. 89-91 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 駒井三千夫, 白井仁, ほか: "腸内フローラが存在しないメナキノン-4(ビタミンK_2)の組織内生成機構の解明"無菌生物. 32. 94-97 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirakawa,H., Ohsaki,Y., Hiwatashi,K., Komai,M., and Furukawa,Y.: ""How do genes express.-Clarification of new functions of nutritional elements using DNA microarray""Boundary. 17 (in Japanese). 30-32 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shirakawa,H., Ohsaki,Y., Hiwatashi,K., Furukawa,Y., and Komai,M.: ""Clarification of new physiological functions of vitamin K using DNA microarray in vitamin K deficient germfree rats.""J. Germfree Life Gnotobiol.. 31 (in Japanese with English Abstract). 50-53 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Komai,M., Shirakawa,H., Ejiri,M., Hiwatashi,K., Ohsaki,Y., Furukawa,Y.: ""Clarification of the mechanisms involved in the menaquinone-4 (vitamin K2) formation from the vitamin K analogues in various tissues""Proceedings for the 5th meeting of Vitamin K & Bone Research. 89-90 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Komai,M., Shirakawa,H., Ejiri,M., Hiwatashi,K., Ohsaki,Y., Mizutani,T., and Furukawa,Y.: ""Clarification of the conversion mechanism of vitamin K analogues to menaquinone-4 (MK-4) in the rats tissues without the participation of bacterial enzyme in the intestine.""J. Germfree Life Gnotobiol.. 32 (in Japanese with English Abstract). 94-97 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Michio Komai, Koki Kojima, Masaki Kato, Ryuta Yamamoto, Hitoshi Shirakawa, Yukio Kitajima, Kyoichi Tadano, Shuichi Kimura, and Yuji Furukawa: "Experimental evidence for menaquinone-4 formation from the achninistered vitamin K1 in rats"(in preparation).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 駒井三千夫, 白川 仁, ほか: "腸内フローラが存在しないメナキノン-4(ビタミンK_2)の組織的生成機構の解明"無菌生物. 32・2. 94-97 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 駒井三千夫, 白川 仁, ほか: "ラットおよびウシの臓器を用いたメナキノン-4生成機構の解析"ビタミン. 76・2. 96-97 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 大崎雄介, 白川 仁, 駒井三千夫, ほか: "DNAマイクロアレイを用いたビタミンK標的遺伝子の検索"ビタミン. 76・3. 165-166 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 白川仁, 古川勇次, 駒井三千夫 他: "無菌ビタミンK欠乏ラットを用いたビタミンKの新規生理作用の検索-DNAマイクロアレイによるアプローチ-"無菌生物. 31・2. 50-53 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 駒井三千夫, 白川仁, 古川勇次, 他: "組織内メナキノン-4生成機構の解析"ビタミン. 75・4. 237-237 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 駒井三千夫, 白川仁, 古川勇次, 他: "ラットおよびウシの臓器を用いたメナキノン-4生成機構の解析"ビタミン. 76・2. 96-97 (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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