Wednesday, March 11, 2009

Are the MK-4 and MK-7 Forms of Vitamin K2 Equivalent?

The vitamin K found in food can be divided into two categories: phylloquinone
(K1) and menaquinone (K2). K1 is concentrated in leafy greens and other green vegetables. K2 can be further subdivided into menaquinone-4 through -14. The number represents the length of the side chain attached to the napthoquinone ring. Menaquinone-"X" can be abbreviated MK-"X". MK-4 is the type synthesized by animals for their own use from K1 (and from MK-7 in rats). MK-5 through MK-14 are synthesized by bacteria. MK-7 in particular is made in large amounts by the bacterium Bacillus subtilis that ferments the infamous Japanese condiment natto. It's also sold as a supplement. Animals concentrate MK-4 in a number of organs, with smaller amounts of K1. Certain organs such as the brain, pancreas and salivary gland show an overwhelming preference for MK-4 over K1 in rodents and humans. The liver is a notable exception; in some animals, including humans, it concentrates longer menaquinones to a greater extent than MK-4 if they're present in the diet.

As far as I can tell, MK-4 is capable of performing all the functions of vitamin K. MK-4 can even activate blood clotting factors, which is a role traditionally ascribed to vitamin K1. Babies are often born clotting deficient, which is why we give newborns vitamin K1 injections in the U.S. to prevent hemorrhaging. In Japan, they give children MK-4 to prevent hemorrhage, an intervention that is very effective. Could that have to do with the fact that Japan has half the infant mortality rate of the U.S.?

Certain cultures would have had a predominance of MK-4 over other forms of vitamin K in the diet, which supports the idea that MK-4 can stand nearly alone. These cultures include heavy consumers of dairy like the Masai. Humans go through one of their most critical growth phases-- infancy-- with most of their vitamin K coming from MK-4. Colostrum, the first milk to come out, is particularly rich in MK-4.

Vitamin K is required to activate certain types of proteins, called Gla proteins. Gla stands for gamma-carboxyglutamic acid, a modified amino acid that's synthesized using vitamin K (by a reaction called gamma-carboxylation). Gla proteins are important: the class includes MGP, osteocalcin and blood clotting factors, important for keeping arteries clear, bones strong and blood clotting correctly.

I've said before that vitamin K's function is to carboxylate Gla proteins. In fact, that's a gross oversimplification. Research on vitamin K2 is turning up new functions all the time. One of the more exciting things that's been discovered is that it acts like hormone, activating a nuclear receptor called the steroid and xenobiotic receptor (SXR) and thereby influencing the expression of a number of genes. This puts it in the same category as vitamin A and D. It also acts as an antioxidant, a cofactor for sphingolipid synthesis in the brain, and an activator of protein kinase A signaling. These are all functions that have been studied in the context of MK-4, and for most of them, no one knows whether MK-7 has equivalent effects.

I'm always on the lookout for studies that can shed light on the question of whether MK-4 and MK-7 are equivalent. MK-7 is able to activate clotting factors and osteocalcin, so it can clearly function as a cofactor for gamma-carboxylation in some contexts. Osteocalcin is a Gla protein that's important for bone health. MK-7 supposedly hangs out in the blood for longer than MK-4 in humans, which is one of the things MK-7 supplement manufacturers like to mention, but these findings were conducted by MK-7 supplement vendors and the results have not been published. Interestingly, MK-4 and MK-7 have the exact same plasma half-life in rats, so I think the human experiment should be repeated. In any case, a longer plasma half-life is not evidence for superiority of one form over another in my opinion.

Today, I found another difference between MK-4 and MK-7. I was reading a paper about SXR-independent effects of vitamin K2 on gene expression. The investigators found that MK-4 strongly activates transcription of two specific genes in osteoblast cells. Osteoblasts are cells that create bone tissue. The genes are GDF15 and STC2 and they're involved in bone and cartilage formation. They tested K1 and MK-7, and in contrast to MK-4, they did not activate transcription of the genes in the slightest. This shows that MK-4 has effects on gene expression in bone tissue that MK-7 doesn't have.

I tend to think there's a reason why animals synthesize MK-4 rather than other forms of vitamin K2. Vitamin K2 MK-4 seems to be able to perform all the functions of vitamin K, including activating Gla proteins, participating in sphingomyelin synthesis, binding SXR, and activating transcription through protein kinase A. That's what you would expect for an animal that had evolved to use its own form of K2. Investigators haven't tested whether MK-7 is capable of performing all these functions, but apparently there's at least one it cannot perform.

I'd bet my bottom dollar there are other important functions of MK-4 that have not yet been identified, and functions whose full importance has not yet been appreciated. There's no way to know whether MK-7 can fully stand in for MK-4 as long as we don't know all of MK-4's functions. I also think it's worth mentioning that MK-4 is the only form of vitamin K2 that's been shown to reduce fracture risk in clinical trials.

That being said, MK-7 may still have a place in a healthy diet. Just because it can't do everything MK-4 can, doesn't mean it has no role. It may be able to fill in for MK-4 in some functions, or reduce the dietary need for MK-4. But no one really knows at this point. Hunter-gatherers would have had a source of longer menaquinones, including MK-7, from livers. So it's possible that we're adapted to a modest MK-7 intake on top of MK-4.


  1. Awesome information on K2.several studies on Vitamin K2 specifically has been found to promote bone metabolism and reduce the incidence of fracture in osteoporosis.Again Thanks Alot.
    Vitamin k2 sources

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