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

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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.