All About Vitamin D

Let’s Learn All About Vitamin D!

Before we begin, do this quick test. Sit down and push hard with your fingers against each of the shin bones of your legs. Then push hard against your sternum (breast bone). If two or three of those bones were painful to your strong push, you have a quick indication that you’re not getting enough Vitamin D. Read on.

750,000,000 years ago

Back in the day, single-cell life forms (various kinds of plankton) floated around in the waters of our planet. As part of their evolution, they learned a trick that has become essential for almost all of the life that came afterwards. This trick involves taking up calcium to create either an exoskeleton or an endoskeleton; that is, a hard, bony exterior or interior. The hormone that regulates the uptake and use of calcium is called Vitamin D, or calciferol.

For most creatures, calciferol is, almost without exception, unavailable in food; that is, almost all life on the planet makes calciferol from sunlight. This statement questions the notion of calciferol as a vitamin, since vitamin means a micro-nutrient that our bodies cannot make and must obtain in diet. Of course, humans can and do manufacture Vitamin D as a result of skin exposure to sunlight, or more specifically, to UV-B rays. However, there are two issues that we must face in this regard. First of all, it is difficult to obtain sufficient amounts of sun exposure the year round in temperate climates. Second, even during those times of year when individuals could obtain sufficient sun exposure, the use of sun screens and plain old avoidance severely limits the amount of natural calciferol that is produced.

Assuming that the widely-accepted “out of Africa” model of human evolution is true, all of mankind originally had darkly pigmented skin, strong in melanin that absorbs excessive sunlight while still allowing for calciferol production. As various waves of early humans moved further north, the amount of melanin in the skin reduced, thereby maintaining the ability to produce calciferol with less sun exposure. There is some reason to believe that the Neanderthals, whose fossil remains often show poor posture and bent legs, may have had poor calciferol status; and this could have been a factor in their ultimate extinction. The modern name for the weakened bones that are due to poor Vitamin D status is rickets.

The most northerly-dwelling humans, the Inuit, traditionally obtained Vitamin D from a diet of marine mammals and oily, cold-water fish, which concentrate calciferol. While the historical distribution of skin pigmentation associates lighter skin with more northerly climates, it is common now to find people of more recent African descent living in countries like Sweden, Canada, the Northern United States, and so forth. Darker-skinned individuals living at higher latitudes are even at more risk for poor Vitamin D status than their lighter-skinned neighbors. Since they need even more sunlight to produce their own natural supply of calciferol, they can fall prey to higher rates of degenerative conditions associated with lower Vitamin D status, like heart and arterial diseases, diabetes, & cancer.

Variants of Vitamin D

There are a number of variants of Vitamin D. I’ve already introduced the name, calciferol, here; and without any qualifications, calciferol refers to the forms D2 and D3. The table below gives details for the five variants of the vitamin.

Forms of Vitamin D

Vitamin D11:1 compound of D2 and lumisterol
Vitamin D2ergocalciferol
Vitamin D3cholecalciferol
Vitamin D422-dihydroergocalciferol
Vitamin D5sitocalciferol

It is the D3 form that is produced in the skin due to sun exposure, or more specifically, by ultraviolet irradiation of 7-dehydrocholesterol. All of the five forms are steroids, which is to say that they include three 6-carbon rings and one 5-carbon ring. There are a broad range of steroids that are critical to life, including the cholesterols. The molecule, 7-dehydrocholesterol is a precursor to both cholesterol and to Vitamin D3, cholecalciferol. It is stored in the epidermal layer of the skin, to which UV-B light (most potently by light at around 300 nm) is capable of penetrating. It also occurs in the milk of many mammals. In a typical European, 15 to 30 minutes of strong sun exposure is the equivalent of taking 15,000 to 20,000 IUs of Vitamin D3. Contrast this with a “large”  supplement of D3 at around 1,000 IUs only.

Vitamin D3, circulating in the blood, goes to the liver where it is converted to calcidiol. Circulating calcidiol is converted in the kidneys to calcitriol, the active form of the hormone. The “-diol” and “-triol” nomenclatures refer to whether two or three hydroxyl (-OH) groups are present on the molecule. Adding a hydroxyl group is called hydroxylation. It is the calcitriol form of the hormone that binds to something called Vitamin D binding protein, aka gc globulin, in the blood. This is the active form of the vitamin/hormone; everything else is just a precursor. This structure, calcitriol bound to gc globulin, is transported to target organs that play a role in calcium utilization. The conversion of calcidiol to calcitriol is regulated by parathyroid hormone, produced by the parathyroid glands. Calcitriol, bound to gc globulin, regulates the amount of calcium in the blood by two primary pathways: by absorption through the gut, and by release from bone. It is very important to realize that if calcitriol levels go up, to increase calcium in the blood, and if there is insufficient calcium in the diet, calcium will be released from one’s own bone. This is the classic situation for older women who have eroded calcium from their own bones during pregnancy and lactation. It is incredibly important for girls in the growing years between 12 – 21 to get as much calcium into their bones as possible: it is like money in the bank.

Calcitriol can also be produced, not just in the kidneys, but by monocyte macrophages of the immune system. In this role, calcitriol acts as a cytokine to up-regulate the innate immune system. Cytokines are proteins that act as cell signaling carriers. I’ll return to the two sides of the human immune system at another time; but for now, understand that it has two major sides: innate and adaptive. The innate immune system is that set of functions that generally targets invaders like bacteria, fungi, viruses, and parasites. It’s response to these threats is virtually immediate. The adaptive immune system is, in contrast, based upon the recognition of specific invaders using antibodies tuned to proteins that they can attach to. Development of these specific antibodies takes some time, several days after they are first recognized. In any case, calcitriol is a signal to the innate immune system that is, in this case, created by macrophages, which are themselves part of that system.

Blasting and Clasting

Osteoblasts are central to the formation of bone. Osteoclasts are central to the reabsorption of bone. Together, these cells play a role in the restructuring of bone throughout the life of an individual. This is an obviously critical process since the size and shape of one’s skeleton must adapt, especially during the years leading up to adulthood. In humans, we do not shed an outer scaly surface, like snakes. We do not achieve adulthood in a single metamorphosis, like some insects. In a young human individual, this process of internal skeletal reformation is on-going. In a fully-grown adult, the process may slow down; but still, it remains active as part of the aging process and in response to damage, and as we’ll see, certain forms of exercise.

Osteoblasts form a dense and mineralized cross-linked collagen structure that is the essence of living bone matter. The osteoblasts lay down this matrix and mineral structure; and the osteoclasts break it down. The proper balance between the two is critical to healthy bone. Osteoblasts are formed from mesenchymal stem cells. Osteoclasts are formed by the self-fusion of monocyte macrophages. This brings us back to the innate immune system and its range of functions. Here we see that it is playing a role, not just in the destruction of invaders, but also in the absorption of bone. Vitamin D is part of the signaling mechanism for these macrophages. There are other factors in the formation of osteoclasts, including RANKL and M-CSF.

Suffice it to say that things start to get rather complex from this point forward. Since RANKL also plays a role in immune response (it is part of a broader family of cytokines called tumor necrosis factors) to cancers, higher levels of it, during the development of certain cancers (breast, prostate, etc.), can assist in their metastasis into bone. As a consequence, drugs have been developed to reduce RANKL levels during the treatment of these cancers. They are often given together with Vitamin D and calcium to stimulate osteoblasts versus osteoclasts. I’ll leave it to those interested enough to follow up on this avenue of exploration.

One thing that should be reasonably clear so far, however, is that it is not true that simply getting more dietary calcium is either going to increase the level of calcium in the blood or to increase bone density. Instead, the body has to signal for more calcium through the production of calcitriol, and as you’ve seen, this is a relatively complex result of the availability of calciferol and parathyroid hormone signals. In fact, there is some evidence that taking high levels of calcium on its own may increase the risk of heart problems in at least some populations. This implies that proper calcium regulation involves the availability of Vitamin D and calcium together in an appropriate balance.

 The Plot Thickens

The manner in which calcitriol achieves many of its actions for calcium regulation depends upon a nuclear receptor transcription factor called VDR, the Vitamin D Receptor. This implies that calcitriol can, in principle, have an impact on any cell at the DNA level. A transcription factor is a protein that binds to some sequence on a DNA strand and bends the DNA so that another part of the strand (a gene), possibly quite distant from the location at which the binding occurs, is either more or less likely (promoted or inhibited) to be transcribed by RNA polymerase.

Here is something to reckon with: Vitamin D impacts the human genome. The VDR works together with another receptor, which binds to a form of Vitamin A, and then impact hormone response elements on DNA. This puts Vitamin D (calcitriol) into the same class of steroid hormones as

  • estrogen
  • aldosterone
  • thyroid hormone T3
  • Vitamin A, retinol, retinal, retinoic acid, etc.
  • bile acids
  • fatty acids

This brings us to an area of very active research. As already described, calcitriol, like these other hormones, turns genes on and expresses certain proteins; and this can happen in any cell in principle. It is known that calcitriol targets certain cells that play a role in calcium metabolism. So far, so good. What is coming to light is the extent to which calcitriol and VDR interact with other genes to regulate unexpected functions.

These include

  • BAG1, which plays a role in programmed cell death, apoptosis, and in Alzheimer’s;
  • BAZ1B, which plays a role in energy expenditure, oxygen uptake, bone mineral density, and immunity;
  • CAV3, which is involved in regulation of heart muscle for ATP-dependent potassium channels, sodium-calcium exchange, and L-type calcium channels for muscle contraction;
  • MED1, which is involved as a mediator in gene transcription and one of three necessary for viability of the entire organism;
  • MED12, an X-chromosome gene, mutations in which can cause retardation, FG syndrome, Lujan-Fryns syndrome, and prostate and uterine cancers;
  • NCOR1 & NCOR2, genes that plays a role in the down-regulation of DNA expression;
  • NCOA2, a gene involved in the up-regulation of DNA expression;
  • RXRA, a co-factor for Vitamin D gene expression;
  • RUNX1, a gene involved in the maturation of blood cells;
  • RUNX1T1, mutations in which are involve in acute myeloid leukemia;
  • SNW1, involved broadly in steroid hormone gene expression;
  • STAT1, a gene involved in up-regulating other genes triggered by interferons, which themselves turn on immune responses to viral, bacterial, and parasite invaders;
  • ZBTB16, involved in transcription of genes in natural killer T-cells and gamma-delta T-cells.

This is an impressive list of functions; but it becomes more impressive when one considers that it actually represents a cascade of other functions, since each of these genes themselves interact with a host of others. In fact, it has been estimated that calcitriol interacts directly or indirectly with around 6% of the human genome, or roughly 2,000 genes.

A Balance

There is another factor that emerges from our considerations so far: Vitamin D does not function alone, but rather, it acts in concert with other molecules. Vitamin C is essential to the formation of the collagen matrix in bone. Vitamin A is essential to the activity of VDR. Calcium is of the essence in Vitamin D’s functions upon osteoblasts and mineral absorption. And so on. This simply leads me back to one of my consistent themes here; namely, that there is an optimum or sweet spot in micro-nutrition. Everything works together around a certain balance. Too much or too little of one item is, at best, ineffective, and at worst upsets that overall balance. This balance is not just in a single dimension, like the playground teeter-totter. Instead, it is a balance across multiple dimensions and upsetting it can yield various forms of degenerative condition in the long term. Simply taking, say, calcium supplements because you think that will be good for your bones is possibly going to do more harm than good.

Ideally, we could achieve and maintain this optimal balance with an appropriate combination of diet and exercise. Unfortunately, there are so many factors in the modern world that work against us that getting and holding such a balance is unusual.

Three of the most common cancers, of the prostate, colon, and breast, are strongly dependent upon Vitamin D status. In the absence of sun exposure, supplementation with at least 1,000 IUs of Vitamin D per day can reduce the risk of these. The risk of metastasis of breast cancer is 94% higher in women with low Vitamin D status; and these women also have a 75% higher risk of dying from this cancer. Men with low Vitamin D status have a three-times higher risk of prostate cancer. Both men and women with low Vitamin D levels have a 50% higher risk of colorectal cancer. These are just some examples of how this balance can become tilted to the negative.

Broadly speaking, there are strong correlations between one’s latitude to the north or south of the tropics and the incidence of cancers, heart disease, and seasonal viral infections. The winter months are, by definition, “flu season”. Vitamin D’s role in activating STAT1 is now assumed to play a significant part in immunity; and in contrast, lowered Vitamin D status during the winter months plays a role in weakened immune responses to seasonal virus infections. These non-classical aspects of Vitamin D and its role in immunity are now becoming more well-known.

There is more to the balance associated with Vitamin D than might meet the eye, even in its simple role of regulating calcium. There have been studies that show that high Vitamin D status can lead to negative consequences for heart health. It turns out that this is true if Vitamin D is not taken together with proper amounts of Vitamins A & K. Calcitriol, at high levels on its own, can lead to calcification of soft tissues that ought not to be calcified. This is not dietary Vitamin D, as such. [Recall that calcitriol is made from calcidiol which is made from cholecalciferol. These studies, like the one in the video that follows, are based upon injections of the active form of the hormone.] Still, it is worth a cautionary note that driving up Vitamin D levels on their own can be counter-productive. Vitamin K protects soft tissues from calcification, and Vitamin A (more specifically, retinoic acid) helps regulate calcitriol’s effects.

It is important to be careful; and as I’ve mentioned before and will state once more: a balance is essential in supplementation. It is not sufficient simply to reach for a bottle of calcium or Vitamin D or what have you at the supermarket and expect beneficial results. It is important to use a scientifically constructed blend of supplements that work together synergistically. The following video addresses the issue of Vitamin D without a balance of Vitamins A & K.

Michael Holick

It would not be appropriate to go further on the Vitamin D story without specific reference to Michael Holick. Holick is almost single-handedly responsible for much of the current scientific understanding of Vitamin D. I heartily encourage you to read the brief monograph on Dr. Holick in the referenced Wikipedia article; and if you are interested, go further and read The Vitamin D Solution. You’ll find a wide set of recommendations on daily intake values based on age, sex, and other factors. For example, because obese individuals tend to sequester Vitamin D in fat cells, Dr. Holick recommends that overweight individuals take 2 to 3 times the daily values of adults of proper weight; that is, 2 to 3 times more than 1,000 to 2,000 IUs per day.

This simple recommendation does not show up on the RDAs published by government, and yet, it could save your life if you are, for example, over-weight and living north of the 39th parallel. Another qualification applies to those taking statin drugs to reduce cholesterol. Since cholecalciferol is derived from a form of cholesterol through UV-B irradiation, statins can reduce the production of Vitamin D3 from sun exposure. Another problematic and ironic side-effect of statins is that something good for heart health is limited by their use. As Christiane Northrup, MD writes in the NY Times: “This information can save your life. Really.” To this, I have not much to add.

I don’t, but others do. Check out the Vitamin D Wiki for the truth of this.

Get Your Vitamin D

If you are over 13, you should be getting at least 1,500 IUs of Vitamin D per day. The best way is through sun exposure. If it’s summer, take off your hat, take off your shirt, don’t slather yourself with sun screen, and get outside for 15-30 minutes a day. If it’s winter and you live north of the 39th parallel, then make sure that you are supplementing with Vitamin D3 in a broad spectrum multivitamin with the proper cofactors for the vitamin; e.g., Vitamins A, C, zinc and calcium. Doing this is part of your best defense against those degenerative conditions that are now responsible for 90% of non-accidental deaths.

I can offer my own testimony in this regard. I started to take a proper and effective wide spectrum multivitamin over a year ago now and I have not been ill once in that time. Having lived most of my life in Canada at around the 51st parallel, I cannot begin to express how unusual that is. Even now, I live right at the 39th parallel near Denver CO, and the winters here are not much better in terms of sun exposure. As I write this, it’s New Year’s Day, 2015. I’m about to go for a four-mile run in yet another heavy snow storm. I love this kind of weather, but the sun is little more than a dull disk in the heavy gray cloud deck. I won’t be getting much sun exposure under my four layers of spandex, cotton, wool and nylon. Back in Canada, there would be months either side of the winter solstice when I’d wake in the dark, go to work in the dark, drive home in the dark. When I was young, my mother used to force feed me a foul concoction of cod liver oil, a tablespoon a day. It was awful stuff, but now I’m glad that she did. Gladly, the Vitamin D3 supplements that I use these days are nothing at all like that dark, fishy goop.

All I can say to you is “get your Vitamin D”. Oh, and your exercise.

More on that later.

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