VITAMINS

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Although most of the menaquinone analogues (MK-n = VK ₂) are synthesized by microorganisms, we have reported that a unique synthesis of MK-4 occurs through the conversion of orally ingested VK ₁or MK-n in the major tissues of germfree rats and mice which lack their intestinal microbiota. Therefore, this study was undertaken to clarify the physiological role of MK-4 present in various tissues of the body. At first, the expression of genes in the liver and testis of rats was examined under vitamin K-deficient conditions using an exhaustive DNA microarray. Under vitamin K-deficient conditions, the liver showed an increase in the expression of genes involved in the acute inflammatory response and the testis showed a decrease in the expression of genes involved in the biosynthesis of cholesterol and steroid hormones. MK-4 was found to exert an anti-inflammatory action in the liver by suppressing the secretion of inflammatory cytokines. MK-4 suppressed the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of nuclear factor κB activation through the repression of IKK α ⁄ β phosphorylation. Rats fed a MK-4-supplemented diet for five weeks had significantly higher plasma and testis testosterone levels than control rats. The protein level of cholesterol side-chain cleavage enzyme (Cyp11a = P450scc), a limiting enzyme in the synthesis of steroids, especially sex hormones, in the testis was higher in the MK-4-supplemented group than in the control group. MK-4 was found to stimulate testosterone synthesis in vivo and in vitro . MK-4 played a novel role in stimulating testosterone synthesis in I-10 cells through regulation of cAMP⁄ PKA signaling pathway.

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We examined the effects of linoleic acid on the activities of rat small intestinal mucosa β- carotene 15,15’-monooxygenase (BCO1) and recombinant murine BCO1. When β-carotene was the substrate, the activity of the mucosal BCO1 with 1 mM linoleic acid was higher than that without linoleic acid. When β-cryptoxanthin was the substrate, the activity of the mucosal BCO1 was not changed by the addition of linoleic acid. When β-carotene was the substrate, the activity of a mixture of recombinant BCO1 and the mucosal BCO1 was lower than the sum of the activity of each BCO1. However, in the presence of linoleic acid, the activity of the mixture of both BCO1s was higher than the sum of the activity of each BCO1. When β-cryptoxanthin was the substrate, the activity of the mixture of both BCO1s was higher than the sum of the activity of each BCO1. These results suggest that when β-carotene is the substrate, BCO1 is inhibited by intestinal mucosa components, but this inhibition of BCO1 activity by intestinal mucosa components could be released by the addition of linoleic acid to the mixture. These results also suggest that BCO1 activity is stimulated by intestinal mucosa components when β-cryptoxanthin is the substrate.

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