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Vitamin K is required for the carboxylation of Gla-proteins in the liver (coagulation factors) and extra-hepatic tissues, such as bone (osteocalcin, OC), and arterial wall (matrix Gla-protein, MGP). Although the coagulation factors are essentially fully carboxylated under normal conditions, 10–40 % of OC and MGP remains undercarboxylated. We were therefore interested to study the dose–response effects of extra intake of menaquinones on the carboxylation of the extra-hepatic Gla-proteins. A total of forty-two healthy Dutch men and women aged between 18 and 45 years were randomised into seven groups to receive: placebo capsules or menaquinone-7 (MK-7) capsules at a daily dose of 10, 20, 45, 90, 180 or 360 μg. Circulating uncarboxylated OC (ucOC), carboxylated OC (cOC) and desphospho-uncarboxylated MGP were measured by ELISA. The ucOC:cOC ratio was calculated from circulating ucOC and cOC values. Endogenous thrombin potential and peak height were determined by calibrated automated thrombography. To increase the statistical power, we collapsed the treatment groups into three dosage groups: placebo, low-dose supplementation (doses below RDA, Commission Directive 2008/100/EC), and high-dose supplementation (doses around RDA, Commission Directive 2008/100/EC). MK-7 supplementation at doses in the order of the RDA (Commission Directive 2008/100/EC) increased the carboxylation of circulating OC and MGP. No adverse effects on thrombin generation were observed. Extra MK-7 intake at nutritional doses around the RDA (Commission Directive 2008/100/EC) improved the carboxylation of the extra-hepatic vitamin K-dependent proteins. Whether this improvement contributes to public health, i.e. increasing the protection against age-related diseases needs further investigation in specifically designed intervention trials.

Vitamin K and its essential role in coagulation (vitamin K [Koagulation]) have been well established and accepted the world over. Many countries have a Recommended Daily Intake (RDI) for vitamin K based on early research, and its necessary role in the activation of vitamin K-dependent coagulation proteins is known. In the past few decades, the role of vitamin K-dependent proteins in processes beyond coagulation has been discovered. Various isoforms of vitamin K have been identified, and vitamin K2 specifically has been highlighted for its long half-life and extrahepatic activity, whereas the dietary form vitamin K1 has a shorter half-life. In this review, we highlight the specific activity of vitamin K2 based upon proposed frameworks necessary for a bioactive substance to be recommended for an RDI. Vitamin K2 meets all these criteria and should be considered for a specific dietary recommendation intake.

Osteocalcin (OC) is a vitamin K-dependent protein found in bone and in circulation. High serum γ-carboxylated OC reflects a high, and high uncarboxylated OC (ucOC) reflects a low vitamin K status. A revolutionary hypothesis is that ucOC acts as a hormone improving glucose handling and reducing fat mass. The objective was to test the logical extrapolation of the ucOC hormone hypothesis to humans that elevated ucOC is associated with higher body weight, BMI and fat mass. In a cross-sectional analysis, the associations of vitamin K status with circulating adiponectin and body composition were investigated in 244 postmenopausal women (study I). The effects of vitamin K treatment on adiponectin, body weight and BMI were investigated in archived samples from forty-two young men and women who received varying doses of menaquinone-7 during 12 weeks (study II) and from a cohort of 164 postmenopausal women who participated in a 3-year placebo-controlled trial on 45 mg menaquinone-4 (MK-4) (study III). No association was found between vitamin K status and circulating adiponectin before or after vitamin K supplementation. A higher carboxylation of OC was significantly correlated with lower body weight, BMI and fat mass of the trunk. Women taking MK-4 maintained their baseline body weight and BMI, whereas women taking placebo showed significant increases in both indices. These findings demonstrate that a high vitamin K status of bone has no effect on circulating adiponectin in healthy people and long-term vitamin K supplementation does not increase weight in healthy postmenopausal women.

Summary The present study investigated the risk of incident hip fractures according to serum concentrations of vitamin K 1 and 25-hydroxyvitamin D in elderly Norwegians during long-term follow-up. The results showed that the combination of low concentrations of both vitamin D and K 1 provides a significant risk factor for hip fractures. Introduction This case-cohort study aims to investigate the associations between serum vitamin K 1 and hip fracture and the possible effect of 25-hydroxyvitamin D (25(OH)D) on this association. Methods The source cohort was 21,774 men and women aged 65 to 79 years who attended Norwegian community-based health studies during 1994–2001. Hip fractures were identified through hospital registers during median follow-up of 8.2 years. Vitamins were determined in serum obtained at baseline in all hip fracture cases ( n  = 1090) and in a randomly selected subcohort ( n  = 1318). Cox proportional hazards regression with quartiles of serum vitamin K 1 as explanatory variable was performed. Analyses were further performed with the following four groups as explanatory variable: I: vitamin K 1  ≥ 0.76 and 25(OH)D ≥ 50 nmol/l, II: vitamin K 1  ≥ 0.76 and 25(OH)D < 50 nmol/l, III: vitamin K 1  < 0.76 and 25(OH)D ≥ 50 nmol/l, and IV: vitamin K 1  < 0.76 and 25(OH)D < 50 nmol/l. Results Age- and sex-adjusted analyses revealed an inverse association between quartiles of vitamin K 1 and the risk of hip fracture. Further, a 50 % higher risk of hip fracture was observed in subjects with both low vitamin K 1 and 25(OH)D compared with subjects with high vitamin K 1 and 25(OH)D (HR 1.50, 95 % CI 1.18–1.90). The association remained statistically significant after adjusting for body mass index, smoking, triglycerides, and serum α-tocopherol. No increased risk was observed in the groups low in one vitamin only. Conclusion Combination of low concentrations of vitamin K 1 and 25(OH)D is associated with increased risk of hip fractures.

Key enzyme in vitamin K metabolism Vitamin K, an important factor in blood clotting and bone metabolism, is present in the diet principally as phylloquinone (PK) from plants. One form of the vitamin, menaquinone-4 or MK-4, has a highly specific tissue distribution in the brain, kidney and pancreas in humans and in rats, suggestive of local synthesis from phylloquinone. An enzyme catalysing that synthesis has now been identified: UbiA prenyltransferase containing 1 (UBIAD1) is a human homologue of an Escherichia coli enzyme. Previously its function was unclear, although it is a candidate gene in Schnyder crystalline corneal dystrophy. The discovery of a human MK-4 enzyme able to biosynthesize the hormonally active form of vitamin K is of relevance to work on human vitamin K requirements and bone health. These authors identify the human enzyme responsible for menaquinone-4 biosynthesis, a naturally occurring form of vitamin K. They find that UbiA prenyltransferase containing 1 , a human homologue of a prenyltransferase gene from Escherichia coli , encodes an enzyme that can convert vitamin K derivatives into menaquinone-4. Vitamin K occurs in the natural world in several forms, including a plant form, phylloquinone (PK), and a bacterial form, menaquinones (MKs). In many species, including humans, PK is a minor constituent of hepatic vitamin K content, with most hepatic vitamin K content comprising long-chain MKs. Menaquinone-4 (MK-4) is ubiquitously present in extrahepatic tissues, with particularly high concentrations in the brain, kidney and pancreas of humans and rats 1 , 2 , 3 . It has consistently been shown that PK is endogenously converted to MK-4 (refs 4–8 ). This occurs either directly within certain tissues or by interconversion to menadione (K 3 ), followed by prenylation to MK-4 (refs 9–12 ). No previous study has sought to identify the human enzyme responsible for MK-4 biosynthesis. Previously we provided evidence for the conversion of PK and K 3 into MK-4 in mouse cerebra 13 . However, the molecular mechanisms for these conversion reactions are unclear. Here we identify a human MK-4 biosynthetic enzyme. We screened the human genome database for prenylation enzymes and found UbiA prenyltransferase containing 1 ( UBIAD1 ), a human homologue of Escherichia coli prenyltransferase menA . We found that short interfering RNA against the UBIAD1 gene inhibited the conversion of deuterium-labelled vitamin K derivatives into deuterium-labelled-MK-4 (MK-4-d 7 ) in human cells. We confirmed that the UBIAD1 gene encodes an MK-4 biosynthetic enzyme through its expression and conversion of deuterium-labelled vitamin K derivatives into MK-4-d 7 in insect cells infected with UBIAD1 baculovirus. Converted MK-4-d 7 was chemically identified by 2 H-NMR analysis. MK-4 biosynthesis by UBIAD1 was not affected by the vitamin K antagonist warfarin. UBIAD1 was localized in endoplasmic reticulum and ubiquitously expressed in several tissues of mice. Our results show that UBIAD1 is a human MK-4 biosynthetic enzyme; this identification will permit more effective decisions to be made about vitamin K intake and bone health.

Background/Objectives: Post-menopausal women are at an increased risk of developing cardiovascular disease. Menaquinone-7 (MK-7) is a fat-soluble vitamin involved in coagulation and maintaining vascular health. The aim of the post hoc analysis of this one-year study is to investigate the effects of MK-7 supplementation on the vascular parameters in pre-, peri-, and post-menopausal women. Methods: In a clinical intervention trial (NCT02404519), a total of 165 women with a low vitamin K status received either 180 µg of MK-7 daily (n = 82) or a matching placebo (n = 83) for one year. Established vascular parameters were measured before and after one year of vitamin K2 supplementation. Pre-, peri-, and post-menopausal women were subdivided according to arterial stiffness, with a high b-stiffness index defined as being greater than the overall median of 9.83. Results: The post hoc analyses showed a significant decrease in desphospho-uncarboxylated matrix Gla protein (dp-ucMGP) plasma levels after MK-7 supplementation (pre/peri, p = 0.009; post, p < 0.001). MK-7 treatment significantly attenuated vascular stiffness in post-menopausal women (placebo +49.1% ± 77.4; MK-7 +9.4% ± 67.1; p = 0.035). Post-menopausal women with a high stiffness index showed significantly improved vascular markers after MK-7 treatment, e.g., a decreased blood pressure at brachialis (−3.0% ± 9.0; p = 0.007) and an increased distensibility coefficient (+13.3% ± 32.3; p = 0.040). Conclusions: Our results confirm that menopause affects vascular health status. Post-menopausal women with an increased stiffness benefit most from MK-7 supplementation, with a significantly improved blood pressure. Further research is needed to unravel the beneficial effects of MK-7 in post-menopausal women.

Fat-soluble vitamin deficiency remains a challenge in cystic fibrosis (CF), chronic pancreatitis, and biliary atresia. Liposomes and cyclodextrins can enhance their bioavailability, thus this multi-center randomized placebo-controlled trial compared three-month supplementation of fat-soluble vitamins in the form of liposomes or cyclodextrins to medium-chain triglycerides (MCT) in pancreatic-insufficient CF patients. The daily doses were as follows: 2000 IU of retinyl palmitate, 4000 IU of vitamin D3, 200 IU of RRR-α-tocopherol, and 200 µg of vitamin K2 as menaquinone-7, with vitamin E given in soybean oil instead of liposomes. All participants received 4 mg of β-carotene and 1.07 mg of vitamin K1 to ensure compliance with the guidelines. The primary outcome was the change from the baseline of all-trans-retinol and 25-hydroxyvitamin D3 concentrations and the percentage of undercarboxylated osteocalcin. Out of 75 randomized patients (n = 28 liposomes, n = 22 cyclodextrins, and n = 25 MCT), 67 completed the trial (89%; n = 26 liposomes, n = 18 cyclodextrins, and n = 23 MCT) and had a median age of 22 years (IQR 19–28), body mass index of 20.6 kg/m2 [18.4–22.0], and forced expiratory volume in 1 s of 65% (44–84%). The liposomal formulation of vitamin A was associated with the improved evolution of serum all-trans-retinol compared to the control (median +1.7 ng/mL (IQR −44.3–86.1) vs. −38.8 ng/mL (−71.2–6.8), p = 0.028). Cyclodextrins enhanced the bioavailability of vitamin D3 (+9.0 ng/mL (1.0–17.0) vs. +3.0 ng/mL (−4.0–7.0), p = 0.012) and vitamin E (+4.34 µg/mL (0.33–6.52) vs. −0.34 µg/mL (−1.71–2.15), p = 0.010). Liposomes may augment the bioavailability of vitamin A and cyclodextrins may strengthen the supplementation of vitamins D3 and E relative to MCT in pancreatic-insufficient CF but further studies are required to assess liposomal vitamin E (German Clinical Trial Register number DRKS00014295, funded from EU and Norsa Pharma).

Vitamin K acts as a coenzyme of carboxylase, catalyzing the carboxylation of several vitamin K dependent proteins. Beyond its well-known effects on blood coagulation, it also exerts relevant effects on bone and the vascular system. In this review, we point out the relevance of an adequate vitamin K intake to obtain sufficient levels of carboxylated (active form) vitamin K dependent proteins (such as Osteocalcin and matrix Gla protein) to prevent bone health. Another bone-related action of Vitamin K is being a ligand of the nuclear steroid and xenobiotic receptor (SXR). We also discuss the recommended intake, deficiency, and assessment of vitamin K. Furthermore, we review the few available studies that have as pre-specified outcome bone fractures, indicating that we need more clinical studies to confirm that vitamin K is a potential therapeutic agent for bone fractures.

It has recently been hypothesized that vitamin K could play a role in COVID-19. We aimed to test the hypotheses that low vitamin K status is a common characteristic of patients hospitalized with COVID-19 compared to population controls and that low vitamin K status predicts mortality in COVID-19 patients. In a cohort of 138 COVID-19 patients and 138 population controls, we measured plasma dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP), which reflects the functional vitamin K status in peripheral tissue. Forty-three patients died within 90 days from admission. In patients, levels of dp-ucMGP differed significantly between survivors (mean 877; 95% CI: 778; 995) and non-survivors (mean 1445; 95% CI: 1148; 1820). Furthermore, levels of dp-ucMGP (pmol/L) were considerably higher in patients (mean 1022; 95% CI: 912; 1151) compared to controls (mean 509; 95% CI: 485; 540). Cox regression survival analysis showed that increasing levels of dp-ucMGP (reflecting low vitamin K status) were associated with higher mortality risk (sex- and age-adjusted hazard ratio per doubling of dp-ucMGP was 1.49, 95% CI: 1.03; 2.24). The association attenuated and became statistically insignificant after adjustment for co-morbidities (sex, age, CVD, diabetes, BMI, and eGFR adjusted hazard ratio per doubling of dp-ucMGP was 1.22, 95% CI: 0.82; 1.80). In conclusion, we found that low vitamin K status was associated with mortality in patients with COVID-19 in sex- and age-adjusted analyses, but not in analyses additionally adjusted for co-morbidities. Randomized clinical trials would be needed to clarify a potential role, if any, of vitamin K in the course of COVID-19.

Vitamin K (VK) plays many important functions in the body. The most important of them include the contribution in calcium homeostasis and anticoagulation. Vascular calcification (VC) is one of the most important mechanisms of renal pathology. The most potent inhibitor of this process—matrix Gla protein (MGP) is VK-dependent. Chronic kidney disease (CKD) patients, both non-dialysed and hemodialysed, often have VK deficiency. Elevated uncarboxylated matrix Gla protein (ucMGP) levels indirectly reflected VK deficiency and are associated with a higher risk of cardiovascular events in these patients. It has been suggested that VK intake may reduce the VC and related cardiovascular risk. Vitamin K intake has been suggested to reduce VC and the associated cardiovascular risk. The role and possibility of VK supplementation as well as the impact of anticoagulation therapy on VK deficiency in CKD patients is discussed.