Vitamin D

Definitions & Key takeaways

Vitamin D is a steroid hormone which function is to promote mineralization of new bone. This is accomplished by increasing calcium and phosphate absorption by the intestine and kidneys, and stimulating osteoclast activity in bone, to promote bone remodeling. These actions are carried out together with parathyroid hormone, which shares many of the effects of vitamin D. Vitamin D can be acquired as an inactive intermediate through diet or by synthesis in the skin. Its physiologically active form is found only after hydroxylation in the kidneys by the enzyme 1-alpha-hydroxylase to 1,25-dihydroxycholecalciferol.

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Introduction0:00–0:21

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.

Calcium Regulation0:21–1:36

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.

Synthesis1:36–5:18

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.
When the skin is exposed to sunlight, 7-dehydrocholesterol absorbs ultraviolet B radiation and is converted to previtamin D3 via photolysis.
Then heat generated by cellular metabolic activities causes the previtamin D3 molecule to isomerize or change its shape to form vitamin D3 or cholecalciferol.
The vitamin D3 molecules then enter the blood, and follow the same path as dietary cholecalciferol to the liver, and then to the kidneys.

Control5:18–6:18

Normally total blood calcium is between 8.5 to 10 mg/dl. If calcium levels drop, the parathyroid glands release more parathyroid hormone, which has a number of effects.
Parathyroid hormone increases bone resorption and releases calcium and phosphate ions into the blood. It also acts on the kidneys to increase calcium reabsorption in the loop of henle, the distal convoluted tubule and collecting ducts, while blocking phosphate reabsorption in the proximal tubule.
Finally, parathyroid hormone also causes the renal cells in the proximal tubule to increase synthesis of 1-alpha-hydroxylase which converts calcifediol into active vitamin D.
Decreased levels of phosphate can also trigger the increased synthesis of 1-alpha-hydroxylase. Active vitamin D is then transported by a carrier protein through the blood to various tissues, like the bones, intestines, and kidneys.

Functions6:18–8:32

Because vitamin D is fat-soluble, it diffuses across cellular membranes of these tissues without the help of a transporter.
Inside the cells, it binds to vitamin D receptors in the cytoplasm, which transports it into the nucleus where it stimulates transcription of specific genes and synthesis of proteins.
In the bones, vitamin D functions very similarly to parathyroid hormone by binding to vitamin D receptors on osteoblasts, which are the bone building cells, and gets them to release cytokines.
These cytokines include receptor activator of nuclear factor kappa-B ligand or RANKL for short, and macrophage colony-stimulating factor or M-CSF.
These cytokines help get multiple macrophage precursors to fuse together and form a single osteoclast, which are bone eating cells.
This is kind of like how 5 robot lions join together to form a single Voltron. Osteoclasts breakdown bone, and the two minerals that make up bone - calcium and phosphate - are released into the blood.
In enterocytes, which are the epithelial cells of the small intestine, active vitamin D increases calcium and phosphate absorption by stimulating the synthesis of calbindin D-28K, a calcium-binding protein that can hold four calcium ions and it helps stimulate calcium absorption.
When calcium from food sources diffuses into enterocytes, it binds to calbindin D-28K before being pumped out through the cells’ basolateral membrane and into blood circulation.
Active vitamin D also causes the enterocytes to increase synthesis of sodium-phosphate cotransporters which increase phosphate absorption.
In the kidneys, active vitamin D carries out two similar actions. In principal cells of the distal convoluted tubules, it stimulates the synthesis of calbindin D-28K, allowing more calcium to be reabsorbed from urine.
And in tubular cells of the proximal convoluted tubules, it causes increased synthesis of sodium-phosphate cotransporters on the apical surface, which increase phosphate reabsorption.
Alright, as a quick recap, vitamin D2 is obtained from the diet while vitamin D3 is obtained from the diet or the skin. Both vitamin D2 and D3 are transformed into active vitamin D by the liver and kidneys.

Review8:32–9:15

Activation of vitamin D can be triggered by parathyroid hormone when calcium or phosphate levels are low. Effects of activated vitamin D include stimulating bone resorption, calcium and phosphate absorption in the small intestine, as well as calcium and phosphate reabsorption in the kidneys.
Parathyroid hormone causes a net increase in calcium and decrease in phosphate, while active vitamin D causes an increase in both calcium and phosphate.