Hi, my name's Dr. Ulrich Bishop and welcome to my podcast and videocast station. I really do appreciate you tuning in and today I've got something that's pretty interesting. It's not my usual wheelhouse. I think this one is a bit confusing. But I think it's also super important to work through it. And what I'm wanting to talk about is vitamin K and where that fits in. And the fact that it's a fat soluble vitamin and how there might be an interplay between how we lower cholesterol or alter lipids and can have an impact on vitamin K too. And one. So what is vitamin K? Well, Vitamin K is one of the fat, soluble vitamins. You may know of it because when a baby's born, it gets a jab in the bottom with vitamin K. And the reason that occurs is because it reduces the chance of that infant suffering a bleeding complication. So vitamin K is central in making sure our blood clots. properly. That's not going to be the main area that I'll be talking about today. I'm going to be talking about other aspects where vitamin K is really, really important. When we think about the fat-soluble vitamins, we think about vitamin A, particularly good for retina, vitamin E, particularly good as an antioxidant, the vitamin D, which we know is to do with sun, calcium metabolism, and vitamin K, which I've just told you can be involved with coagulation. And I'm also going to talk about calcification because vitamin K is really important in that. When we think about vitamin K, we think about it as vitamin K1, which is really you're able to obtain vitamin K1 from green. leafy vegetables, cruciferous vegetables, in fact. Vitamin K1 is also referred to as philoquinone. And we know that if someone's on morphine, which is a drug that blocks vitamin K, and we use that to thin the blood to increase the ability or bleeding time for an individual and reduce the chance of them clotting, then we know if those individuals eat cruciferous vegetables, they can muck up with that interaction and offset the benefit or the role of vitamin K. Sorry, warfarin. The second type of vitamin K, I've just mentioned one, philoquinone, is menaquinone. And menaquinone comes in a number of different subtypes. There's a bit of complexity there. I don't want to get caught on that just now, but we will come back and touch base on it. Now, what I'm really keen to discuss primarily is where vitamin K fits in with bone and bone health. Vitamin K facilitates the enzymatic process that allows a protein called osteocalcin to have its effect. And osteocalcin facilitates calcium literally being incorporated into the bone matrix. So osteocalcin is super important to make sure we get calcium in the bones. Vitamin K also appears to have a role in making sure we produce plenty of osteoblasts. Osteoblasts are the cells that build up our bone, and they work almost like an accelerator and a brake with osteoclasts. Osteoblasts building bone, osteoclasts... tending to reabsorb bone. So vitamin K helps in making sure we've got plenty of osteoblasts. Vitamin K also seems to have a role in minimizing or controlling osteoclast genesis or formation. So by reducing or controlling that, then it's facilitating the balance between bone deposition And bone reabsorption, making sure that we don't reabsorb too much bone. So really nice interplay there and super duper important. So when we think about some of these interactions, they are central to making sure that, if you like, bone. is built up where it should be. So where we see calcium where it should be in the bone, but we also, at the same time, by getting calcium in the bone, it seems that we reduce the chance of calcium where it shouldn't be. And one of the places where it shouldn't be is in the aortic valve. So when we're talking about... where vitamin K fits in, we know that it has a role in activating osteocalcin, and that's really helpful for making sure that bone mineralization occurs properly. But that same enzymatic process also carboxylates or activates another protein called matrix GLA protein. Now, by activating or carboxylating matrix GLA protein, we know matrix or MGP matrix GLA protein is a very strong inhibitor of soft tissue calcification so calcium ending up in the wrong place so there's a very important balance there that vitamin k appears to be supporting vitamin k also as i mentioned seems to have a role in helping osteoblasts being differentiated reduces the formation of osteoclasts the cells that eat up bone, and it also has a role at turning down the inflammatory process that occurs literally at the bone surface through a pathway called rankle, which is an inflammatory process. So if we're thinking about that role of vitamin K, we're thinking its presence facilitates calcium in the right place and reduces calcium. in the wrong place. What are the things that we're thinking about where that could be a problem? Well, lack of calcium in the right place is osteoporosis. Too much calcium in the wrong place could be aortic valve disease or aortic stenosis where the valve becomes narrowed because calcium ends up in the leaflets of the valve and make it sticky. Well, do we have any research that supports the vitamin K could be implicated in this? Well, There is a bit of stuff where they've looked at warfarin therapy and its impact on bone health. And this has shown that men in particular, less so women, but men in particular, do seem to have significant impact on normal bone mineralization when treated with warfarin, i.e. vitamin K blocking, reducing osteocalcin, positive effect on bone mineral density. having an effect leading to reduced bone renal density in these people. So pretty important. But what's the angle that I'm particularly interested in here? Well, it turns out that I'm particularly interested in the angle to do with the statins and azetimibe, our lipid managing drugs, because these drugs potentially could impact vitamin, because, well, vitamin K is a lipid-soluble or a lipid-based vitamin, and we're looking to lower the lipids, so it makes sense. In a normal cell, it's really important to understand that acetyl-CoA, which is within the cell, is converted to HMG-CoA reductase. For those who know about statins, They are HMG-CoA reductase inhibitors. So HMG-CoA goes through to mevalinate. Mevalinate goes through a couple of intermediaries, IPP, FPP, GGPP, and is then, with menodione, converted into MK. or menaquinone 4, which is one of the subclasses of vitamin K2 to then have its effect. Now, if we add a statin to the mix, we obviously block that conversion of HMG-CoA through to mevalinate and then the subsequent intermediaries, and so reducing production of vitamin M. Am I aware of any data that's really linked clinical significance of reducing MK4 through statin therapy? No, not at this stage. But it is interesting to think about. And part of the reason why I think it's so interesting to think about is that these days, we really do drive significant LDL or cholesterol lowering in those high-risk individuals. And one of the things we will often do is combine Our statin therapy with an agent called ezetimibe. Well, it turns out when you look at how ezetimibe works, remember the statins work through blocking that enzymatic pathway. When you look at how ezetimibe works, it works through a receptor in the gut to reduce absorption of cholesterol or reabsorption of cholesterol because it's often bile. which contains cholesterol that's passing through the intestine. Well, that reabsorption of cholesterol is through a particular receptor called the NPC1L1 receptor. And it turns out that that very same receptor not only transfers or helps absorb cholesterol, which is our target using azetamide, but it also is. the receptor that helps absorb vitamin K. So if we think about it, we're actually impacting that vitamin K system through two mechanisms. One is through the enzymatic process, HMG-Ki reductase, and therefore reducing production of menequinone-4. The other is reducing vitamin K absorption altogether. The significance of this, we are not 100% sure of, but it is super duper interesting. What we do know is that when we look at lowering cholesterol levels, particularly in high-risk people, particularly with statins, we see calcification as a sign of stability in the coronary arteries. Now, this is a good thing, but it is calcification in tissues where it shouldn't be. Now, could that same process be robbing the bone of the calcium deposition it should really be needing? And could that same process be also impacting the aortic valve by putting calcium in the aortic valve leaflets, leading to stenosis? Again, we don't have clear data on that. We do have some research that's looked at statin, anazetamide, and tracked. People with moderate aortic stenosis have not found a clear uptick in the progression of aortic stenosis from statin and azetimibe. So this is a space where we don't have really solid research data, but we do have really interesting mechanistic ideas where we can see and understand where an HMG-Ki reductase inhibitor may well impact. the production of menaquinone, and where we could postulate or hypothesize that reducing statin reabsorption and at the same time reducing reabsorption of vitamin K2 could similarly have an impact to leave the body relatively deficit of vitamin K1 and 2 with the consequence of less calcium ending up in our bones. and more calcium ending up where it shouldn't be. Well, I'm going to end there. I hope you found that informative and interesting. It's not my usual wheelhouse. It is a super complicated but terribly interesting area. I think we will have to keep a space on it. What would be my recommendation for my own patients? I think I would start to be... letting them know that there can be this interplay, and I'd be inviting them to consider whether they would supplement with a vitamin K supplement if they were already on the lipid lowering regime that I just alluded to. Well, I hope you've enjoyed that. I do wish you the very best. I really appreciate your attention. If you've got any queries or questions, drop us a note at info at drorichbishop.online. Till next time, I hope you live as well as possible. for as long as possible. Take care and bye for now.
