Vitamin D

The blood calcium level stays stable thanks to three hormones: Vitamin D, parathyroid hormone, and calcitonin.

We’ll focus on Vitamin D, which along with parathyroid hormone, helps increase calcium levels, whereas calcitonin helps lower them.

The majority of the extracellular calcium, the calcium in the blood and interstitium, is split almost equally into calcium that’s diffusible and calcium that’s not diffusible.

Diffusible calcium is small enough to diffuse across cell membranes and there are two subcategories.

The first is free-ionized calcium, which is involved in all sorts of cellular processes like neuronal action potentials, contraction of skeletal, smooth, and cardiac muscle, hormone secretion, and blood coagulation, all of which are tightly regulated by enzymes and hormones.

The second category is complexed calcium, which is where the positively charged calcium is ionically linked to tiny negatively charged molecules like oxalate and phosphate, which are small anions, that are found in our blood.

The complexed calcium forms a molecule that’s electrically neutral but unlike free-ionized calcium it’s not useful for cellular processes.

Finally there’s the non-diffusible calcium which is bound to large negatively charged proteins like albumin.

The resulting protein-calcium complex is too large and charged to cross membranes, so the non-diffusible calcium is also uninvolved in cellular processes.

Now, after parathyroid hormone, the metabolically active form of vitamin D, also called calcitriol, is the second most important hormone involved in regulating blood calcium.

Vitamin D is a steroid hormone, which means that it’s made from cholesterol and it’s fat-soluble.

Active vitamin D starts out as one of two metabolically inactive molecules.

Either vitamin D2, or ergocalciferol, which comes from plant sources in our diet, and vitamin D3, or cholecalciferol, which can either come from animal products in our diet, but can also be made in skin cells that are exposed to sunlight.

But since both ergocalciferol and cholecalciferol are physiologically inactive molecules to vitamin D, they have to be modified a bit by the body before they can be used.

Let’s start with molecules coming from the diet.

When vitamin D2 and D3 reach the small intestine, they get packaged along with bile salts into micelles, which get absorbed into the intestinal cells called enterocytes.

Vitamin D2 and D3 are then incorporated into lipoproteins called chylomicrons which get into the lymph and make their way through the lymphatic system and eventually enter the blood.

Vitamin D2 and D3 are fat soluble so they have to be carried around the blood by vitamin D-binding proteins, which take them to the liver.

Vitamin D2 and D3 get into the endoplasmic reticulum of the hepatocyte cells of the liver. That’s where they begin to undergo multiple modifications, so let’s zoom into the endoplasmic reticulum.

First the enzyme 25-hydroxylase adds a hydroxyl group in the 25th position of both molecules.

As a result, vitamin D2 becomes 25-hydroxyergocalciferol, or ercalcidiol, and vitamin D3 becomes 25-hydroxycholecalciferol, or calcifediol.

Ercalcidiol and calcifediol then reenter the blood, once again, bound to vitamin D-binding protein.

Their journey then continues from the liver to the proximal tubules of the kidneys.

They enter the mitochondria of renal cells.

Let’s zoom into the mitochrondria. Here, the enzyme 1-alpha-hydroxylase adds a hydroxyl group to the carbon-1 position of both ercalcidiol and calcifediol, resulting in 1,25 dihydroxyergocalciferol, also called ercalcitriol, and in 1,25 dihydroxycholecalciferol, also called calcitriol.

Both ercalcitriol and calcitriol are commonly called active vitamin D because they both have the same effect on the body’s vitamin D receptors.

Now, let’s follow the journey of Vitamin D3 that’s produced in the skin.

Keratinocytes in the two deep layers of the epidermis - the stratum basale and stratum spinosum - produce 7-dehydrocholesterol, a precursor molecule for cholecalciferol.