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CLARIFICATION OF THE BIOLOGICAL MEANING OF MENAQUINONE-4 SYNTHESIS IN ANIMAL ORGANS

动物器官中甲萘醌-4 合成的生物学意义的澄清

基本信息

批准号：
16580095
负责人：
SHIRAKAWA Hitoshi
金额：
$ 2.43万
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：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Vitamin K (K) is well known for its role in post-translational activation of a family of nascent proteins to Gla-proteins, such as blood clotting factors and bone Gla-proteins. There are two forms of naturally occurring K: Ki, plant-synthesized phylloquinone; and K2, a family of homologues designated as menaquinone-n (MK-n), which are synthesized by microorganisms including intestinal microflora. However, reports indicate that K analogues are converted into MK-4 in various organs outside the gastrointestinal tract without involvement of bacterial enzymes. Although studies indicate that MK-4 has unique functions related to cell differentiation, induction of apoptosis, and stimulation of transcription of a ligand for the nuclear receptor, these cannot totally explain the physiological significance of MK-4 synthesis in diverse tissues. To help elucidate the biological role of MK-4 production, we used germfree rats to eliminate MK-n synthesized by intestinal flora, and identified patterns of gene expression as a function of K status.Wistar germfree rats were fed either K-deficient, Control (normal level of 1(1), Ki-supplemented, or MK-4-supplemented diets. We obtained testicular gene expression profiles using DNA microarray techniques. Expression of genes involved in cholesterol synthesis and isoprenoid metabolism was down-regulated in the K-deficient group compared with Ki-supplemented animals. Quantitative RT-PCR analysis revealed that testicular MK-4 concentrations were positively correlated with expression of CYP11a, a rate-limiting enzyme involved in testicular testosterone synthesis. Moreover, plasma testosterone concentrations were reduced in K-deficient relative to Control and MK-4-supplemented animals. Together, these results suggest that testicular MK-4 could be a key factor involved in steroid hormone synthesis via regulation of gene expression related to steroidogenesis.

维生素K（K）因其在新生蛋白家族翻译后活化为Gla-蛋白（如凝血因子和骨Gla-蛋白）中的作用而众所周知。天然存在的K有两种形式：Ki，植物合成的叶绿醌;和K2，一个被称为甲基萘醌-n（MK-n）的同系物家族，其由包括肠道微生物菌群在内的微生物合成。然而，报告表明，K类似物在胃肠道外的各种器官中转化为MK-4，而不涉及细菌酶。尽管研究表明MK-4具有与细胞分化、诱导凋亡和刺激核受体配体转录相关的独特功能，但这些不能完全解释MK-4合成在不同组织中的生理意义。为了帮助阐明MK-4产生的生物学作用，我们使用无菌大鼠来消除肠道植物群合成的MK-n，并确定作为K状态的函数的基因表达模式。Wistar无菌大鼠被喂食K缺乏、对照（正常水平1（1）、Ki补充或MK-4补充的饮食。我们用DNA微阵列技术获得了睾丸基因表达谱。与补充Ki的动物相比，缺钾组中参与胆固醇合成和类异戊二烯代谢的基因表达下调。定量RT-PCR分析显示，睾丸MK-4浓度与CYP 11 a（一种参与睾丸睾酮合成的限速酶）的表达正相关。此外，相对于对照和MK-4补充动物，K缺乏动物的血浆睾酮浓度降低。总之，这些结果表明，睾丸MK-4可能是一个关键因素参与类固醇激素合成通过调节基因表达与类固醇生成。