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Vitamin K2 (the menaquinones) is a group name for a family of related compounds, generally subdivided into short-chain menaquinones (with MK-4 as the most important member) and the long-chain menaquinones, of which MK-7, MK-8 and MK-9 are nutritionally the most recognized.
All K vitamins are similar in structure: they share a “quinone” ring, but differ in the length and degree of saturation of the carbon tail and the number of “side chains”. The number of side chains is indicated in the name of the particular menaquinone (e.g., MK-4 means that four molecular units - called isoprene units - are attached to the carbon tail) and this influences the transport to different target tissues.
Mechanism of action
The mechanism of action of vitamin K2 is similar to vitamin K1. Traditionally, K vitamins were recognized as the factor required for coagulation, but the functions performed by this vitamin group were revealed to be much more complex. K vitamins play an essential role as cofactor for the enzyme γ-glutamyl carboxylase, which is involved in vitamin K-dependent carboxylation of the gla domain in "Gla proteins" (i.e., in conversion of peptide-bound glutamic acid (Glu) to γ-carboxy glutamic acid (Gla) in these proteins).
Carboxylation of these vitamin K-dependent Gla-proteins, besides being essential for the function of the protein, is also an important vitamin recovery mechanism since it serves as a recycling pathway to recover vitamin K from its epoxide metabolite (KO) for reuse in carboxylation.
Several human Gla-containing proteins synthesized in several different types of tissues have been discovered:
- Coagulation factors (II, VII, IX, X), as well as anticoagulation proteins (C, S, Z). These Gla-proteins are synthesized in the liver and play an important role in blood homeo-stasis.
- Osteocalcin. This non-collagenous protein is secreted by osteoblasts and plays an essential role in the formation of mineral in bone.
- Matrix gla protein (MGP). This calcification inhibitory protein is found in numerous body tissues, but its role is most pronounced in cartilage and in arterial vessel walls.
- Growth arrest-specific protein 6 (GAS6). GAS6 is secreted by leucocytes and endothelial cells in response to injury and helps in cell survival, proliferation, migration, and adhesion.
- Proline-rich Gla-proteins (PRGP), transmembrane Gla-proteins (TMG), Gla-rich protein (GRP) and periostin; whose precise functions are still unexplored.
Vitamin K2 deficiency results in a decreased level of active osteocalcin, which in turn increases the risk for fragile bones. Research also showed that vitamin K2, but not K1 in combination with calcium and vitamin D can decrease bone turnover and that vitamin K2 is essential for the maintenance of bone strength in postmenopausal women.
The Japanese population seems to be at lower risk for bone fractures compared to European and American citizens. This finding would be paradoxical, if levels of calcium consumption were the only factor determining bone density. Studies link Japan's greater levels of BMD to that country's widespread consumption of natto. Increased intake of MK-7 from natto seems to result in higher levels of activated osteocalcin and a significant reduction in fracture risk.
Patients suffering from osteoporosis were shown to have extensive calcium plaques, which impaired blood flow in the arteries. This simultaneous excess of calcium in one part of the body (arteries), and lack in another (bones) – which may occur even in spite of calcium supplementation – is known as the Calcium Paradox. The underlying reason is vitamin K2 deficiency, which leads to significant impairment in biological function of MGP, the most potent inhibitor of vascular calcification presently known. Fortunately, animal research showed that vascular calcification might not only be prevented, but even reversed by increasing the daily intake of vitamin K2. The strongly protective effect of K2 and not vitamin K1 on cardiovascular health was confirmed by, among others, Geleijnse et al. in the Rotterdam Study (2004, see Figure 3) performed on a group of 4,800 subjects. Results of more than 10 years of follow-up were verified, also by Gast et al., who demonstrated that among K vitamins, the long-chain types of K2 (MK-7 through MK-9) are the most important for efficiently preventing excessive calcium accumulation in the arteries.
Absorption profile of different K vitamins
Vitamin K is absorbed along with dietary fat from the small intestine and transported by chylomicrons in the circulation. Most of vitamin K1 is carried by triacylglycerol-rich lipoproteins (TRL) and rapidly cleared by the liver; only a small amount is released into the circulation and carried by LDL and HDL. MK-4 is carried by the same lipoproteins (TRL, LDL, and HDL) and cleared fast as well. The long-chain menaquinones are absorbed in the same way as vitamin K1 and MK-4, but are efficiently redistributed by the liver in predominantly LDL (VLDL). Since LDL has a long half life in the circulation, these menaquinones can circulate for extended times resulting in higher bioavailability for extra-hepatic tissues as compared to vitamin K1 and MK-4. Accumulation of vitamin K in extra-hepatic tissues has direct relevance to vitamin K functions not related to hemostasis.
Dietary sources and adequate intake
In 2012, Canadian health writer Kate Rhéaume-Bleue suggested the Recommended Daily Allowance (RDA) for K vitamins (range of 80-120 µg) might be too low. Earlier suggestions in the scientific literature, which note that the RDA is based on hepatic (i.e. related to the liver) requirements only, date back as far as 1998. This hypothesis is supported by the fact that the majority of the Western population exhibits a substantial fraction of undercarboxylated extra-hepatic proteins. Thus, complete activation of coagulation factors is satisfied, but there doesn’t seem to be enough vitamin K2 for the carboxylation of osteocalcin in bone and MGP in the vascular system. Highest concentrations of vitamin K1 are found in green leafy vegetables, but significant concentrations are also present in non-leafy green vegetables, several vegetable oils, fruits, grains and dairy. In Europe and the USA 60%, or more, of total vitamin K1 intake is provided by vegetables, the majority by green leafy vegetables. National surveys reveal that K1 intakes vary widely. Intakes determined by weighed-dietary Intakes are similar in mainland Britain to the USA with average daily intakes of around 70–80 μg, which is less than the adequate intake for vitamin K. Apart from animal livers, the richest dietary source of long-chain menaquinones are fermented foods (from bacteria not moulds or yeasts) typically represented by cheeses (MK-8, MK-9) in Western diets and natto (MK-7) in Japan. Food frequency questionnaire-derived estimates of relative intakes in the Netherlands suggest that ~90% of total vitamin K intakes are provided by K1, ~7.5 % by MK-5 through to MK-9 and ~ 2.5% by MK-4. Most food assays measure only fully unsaturated menaquinones; accordingly cheeses have been found to contain MK-8 at 10–20 μg/100g and MK-9 at 35–55 μg/100 g.
Dietary intake sources
Vitamin K2 is preferred by the extra-hepatic tissues (bone, cartilage, vasculature) and this may be produced as MK-4 by the animal from K1, or may be of bacterial origin (MK-7, MK-9, and other MK numbers). The latter may be consumed already prepared by bacteria (see below). Discussion is ongoing as to what extent K2 produced by intestinal bacteria contributes to daily vitamin K2 needs. If, however, intestinal bacterial supply was enough to supplement all tissues needing K2, we would not find high fractions of undercarboxylated Gla-proteins in human studies..
Natural K2 is also found in bacterial fermented foods, like mature cheeses and curd. The MK-4 form of K2 is often found in relatively small quantities in meat and eggs. The richest source of natural K2 is the traditional Japanese dish natto made of fermented soybeans and Bacillus subtilis, which provides an unusually rich source of K2 as long-chain MK-7: its consumption in Northern Japan has been linked to significant improvement in K vitamin's status and bone health in many studies. The intense smell and strong taste, however, make this soyfood a less attractive source of K2 for Westerners' tastes. Supplement food companies sell nattō extract, standardized for K2 content, in capsules. It is not known whether B. Subtilis will produce K2 with other legumes (chickpeas, beans, lentils).
Anticoagulants and K2 supplementation
Recent studies found a clear association between long-term anticoagulant treatment (OAC) and reduced bone quality due to reduction of active osteocalcin. OAC might lead to an increased incidence of fractures, reduced bone mineral density/bone mineral content, osteopenia, and increased serum levels of undercarboxylated osteocalcin. Bone mineral density was significantly lower in stroke patients with long-term warfarin treatment compared to untreated patients and osteopenia was probably an effect of warfarin-interference with vitamin K recycling. Furthermore, OAC is often linked to an undesired soft-tissue calcification in both children and adults. This process has been shown to be dependent upon the action of K vitamins. Vitamin K deficiency results in undercarboxylation of MGP. Vascular calcification was shown to appear in warfarin-treated experimental animals within two weeks. Also in humans on OAC treatment, two-fold more arterial calcification was found as compared to patients not receiving vitamin K antagonists. Among consequences of anticoagulant treatment: increased aortic wall stiffness, coronary insufficiency, ischemia, and even heart failure. Arterial calcification might also contribute to systolic hypertension and ventricular hypertrophy. Coumarins, by interfering with vitamin K metabolism, might also lead to an excessive calcification of cartilage and tracheobronchial arteries.
Anticoagulant therapy is usually instituted to avoid life-threatening diseases and a high vitamin K intake interferes with the anticoagulant effect. Patients on warfarin (Coumadin) treatment, or treatment with other vitamin K antagonist drugs, are therefore advised not to consume diets rich in K vitamins. However, the latest research proposed to combine vitamins K with OAC to stabilize the INR (International normalized ratio, a laboratory test measure of blood coagulation).
There is no known toxicity associated with high doses of menaquinones (vitamin K2). Individuals taking anticoagulant medications, such as warfarin (coumarins) should consult their doctor before taking Vitamin K2. Unlike the other fat-soluble vitamins, vitamin K is not stored in any significant quantity in the liver; therefore toxic level is not a described problem. All data available at this time demonstrate that vitamin K has no adverse effects in healthy subjects. The recommendations for the daily intake of vitamin K, as issued recently by the Institute of Medicine, also acknowledge the wide safety margin of vitamin K: “A search of the literature revealed no evidence of toxicity associated with the intake of either K1 or K2”. A point of concern is however the potential interference of K vitamins with OAC treatment. Individuals taking anticoagulant medications, such as warfarin (coumarins) should consult their doctor before taking Vitamin K2. Animal models involving rats, if generalizable to humans, show that MK-7 is well-tolerated.
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