Recent topics in the studies of laboratory of nutrition, Tohoku University: Newly clarified function of vitamin K

Vitamin K (VK) is essential for blood coagulation and bone metabolism in mammals as a Gla-protein activating factor, i.e., VK acts as a cofactor in the posttranslational synthesis of gamma-carboxyglutamic acid (Gla) from glutamic acid (Glu) residues in the nascent proteins. Menaquinone-4 (MK-4) is one of the VK2 analogues, and is well known to have bioactivity in the suppression of bone resorption through apoptosis of osteoclast cells, thus MK-4 is now also used clinically as a therapeutic drug for the osteoporosis. Besides of these well-known functions, MK-4 is strongly presumed to have other novel functions because we have gradually recognized that MK-4 accumulates in various tissues of germfree animals fed an MK-4-free diet. Accordingly, we have focused on clarification of the mechanism of MK-4 formation in several tissues, using both in vitro tissue homogenates (bovine, rats, mice, chicken) and in vivo experiments with rats and mice. To elucidate the biological role of MK-4 production, we used germfree rats to eliminate MK-n synthesized by intestinal flora. Our in vivo results indicate that MK-4 is produced in diverse tissues from ingested vitamin K analogues, including vitamin K1 MK-n (MK-6, MK-7, and MK-10); and VK3 without enzymatic participation of microorganisms in the intestine. In addition to the liver and bone, VK is found in the brain, heart, testis, kidney, pancreas and salivary glands mainly as menaquinone-4 (MK-4). However, the physiological role of MK-4 in these various organs has not been fully understood yet. In the present study we identified genes of which expression is changed in testis under vitamin K deficient condition using DNA microarray. The genes involved in the biosynthesis pathway of cholesterol and steroid hormone were decreased in vitamin K deficient group. The amount of Cyp11a (P450scc) mRNA, rate-limiting enzyme for testosterone synthesis, was positively correlated with the concentration of MK-4 in testis. Moreover, the concentration of testosterone in plasma and testis was decreased in vitamin K deficient group compared with the control and vitamin K supplemented