KIN343 - Vitamin D

Why were New Dietary Reference Intakes established in November 2010?

Assumes no input from sunlight and takes into account new quantitative data

What blood concentration should vitamin D be at? What does it support?

20 ng/mL (50 mM) of 25-OH Vitamin D is required to support good bone health

How did the November 2010 and 1997 DRI’s of Vitamin D differ most significantly?

2010 does NOT support intakes above the DRI — spoke out against public health claims for excessive intakes (from 1997)

How does the DRI of Vitamin D vary across age, gender, and pregnancy/lactation?

Age → increases from 400 in infancy to 600 in adulthood, and peaks in the elderly at 800 IU

Gender → no difference.

Pregnancy/Lactation → no difference. (Remains 600 UI)

What is significant about the distribution of vitamin D requirements in the population? Why is this significant? (3)

1. Intake requirements are normally distributed

2. Estimated Average Requirement (EAR) could be calculated

3. Upper Limit (UL) Recommendations could be made

Why does the RDA of Vitamin D assume that calcium intake is adequate? (3)

The RDAs for Vitamin D are based on requirements for bone health, which requires adequate calcium

What happens to Vitamin D if calcium is inadequate? Why?

No calcium = changes to the metabolism of Vitamin D that no amount of vitamin D can compensate for!

What are the 2 possible sources of vitamin D?

1. Food

2. Endogenous synthesis from sunlight

What are the two major forms of Vitamin D in food? Which is plant and which is food?

Vitamin D2 → ergocalciferol → plant form

Vitamin D3 → cholecalciferol → animal form

Which form does “Vitamin D” refer to? Why?

Refers to both forms → both have similar responses in the both and are both considered inactive

What are two good fortified sources of Vitamin D in food?

Milk and margarine!

What are 5 good non-fortified sources of Vitamin D in food? Which is the best?

1. Butter

2. Milk

3. Cheese

4. Liver

5. Fatty fish (tuna, salmon, sardines are GREAT sources, upwards to 40 ug)

How is Vitamin D absorbed into enterocytes?

Vitamin D is incorporated into micelles and absorbed into enterocytes by diffusion

How much of dietary Vitamin D is absorbed?

50%

What happens to Vitamin D once it enters enterocytes? How does it enter the blood?

Vitamin D is incorporated into chylomicrons in enterocytes → then secreted into lymphatics where it can then travel into the blood

Once Vitamin D reaches the blood, how does it travel in the bloodstream? Where does it go first?

Vitamin D binds to Vitamin D binding proteins → these proteins take it to the liver

How does endogenous synthesis of Vitamin D seasonally differ?

Winter → 1.5 IU of vitamin D/cm/hour

Summer → 6.0 IU of vitamin D/cm/hour (4x higher!)

How does endogenous synthesis of Vitamin D differ based on latitude?

Above 40oN, there is little to no endogenous vitamin D synthesis for 3-4 winter months (and even less at more extreme latitudes)

What kind of vitamin D is synthesized in the skin? How many steps does this take?

Forms Vitamin D3 (cholecalciferol → animal version) → takes 4 steps

What are the 4 steps of Vitamin D3 synthesis?

Cholesterol → 7-dehydrocholesterol → Unstable intermediate (pre-Vitamin D3) → Vitamin D3 (cholecalciferol)

How is 7-dehydrocholesterol synthesized? Where is it secreted to?

From cholesterol in sebaceous glands of the skin and secreted into the dermis and epidermis

What happens when 7-dehydrocholesterol is struck by UV light?

UVB rays cause the formation of the unstable intermediate (previtamin D3)

How does cholecalciferol (VitD3) form from the unstable intermediate?

The unstable intermediate undergoes thermal isomerization to form VitD3

How is the newly formed cholecalciferol absorbed from the skin? Where does it travel to?

Enters the blood due to its strong affinity for the Vitamin D binding proteins → travels in the blood to the liver for activation

If high levels of Vitamin D in the body can be toxic, why can you spend all day in the sun and not develop Vitamin D toxicity?

Endogenous Vitamin D synthesis is a self-limiting process

In what two ways is the endogenous synthesis of Vitamin C self-limited by the body?

1. Once Vitamin D binding proteins are saturated, Vitamin D stops entering the body and stays on the skin (can be flaked off)

2. When the unstable intermediates keep getting struck by UVB rays, it is converted to other compounds that do not have Vitamin D activity (and cannot bind the VitD binding protein)

What two alternative products form from the unstable intermediate?

1. Lumisterol

2. Tachysterol

What do both Dietary and Endogenous Vitamin D require before they can be used?

They must be Activated! (Currently inactive) → need to be hydroxylated twice!

How do the liver/kidney differ from most organs in terms of Vitamin D activation?

Liver/kidney activate Vitamin D for sharing, while most organs activate Vitamin D but keep the Vitamin D to themselves?

Compare the half-lives of 25(OH) vitamin D to that of 1,25(OH)₂Vitamin D

25(OH) Vitamin D → 2-3 week long half-life!

1,25(OH)₂ Vitamin D → 4-6 hour long half-life!

Summarize the transformation of cholecalciferol starting from when it enters the blood to when it is fully activated

Enters blood → Enters liver, becomes hydroxylated once → enters blood → enters kidney, becomes hydroxylated a second time → enters blood and goes to organs 

What enzymes do the liver and kidney express to allow for the transformation of Vitamin D?

Liver → 25-hydroxylase (highest expression of this enzyme in the body, but other organs still express it)

Kidney → 1a-hydroxylase (highest expression of this enzyme in the body, but other organs have a tiny bit of expression)

What is the major function of Active Vitamin D (1,25(OH)₂ Vit D)?

Increasing blood calcium concentrations!

In what three ways does vitamin D increase blood calcium concentration?

1. Increase intestinal absorption of calcium

2. Increase kidney reabsorption of calcium

3. Increase bone resorption of calcium

At what two levels can Vitamin D regulated blood calcium?

Genomic and Membrane (non-genomic)

What is the effect of a transcription factor?

Can induce or repress gene transcription!

How can vitamin D act genomically to alter expression?

Active Vitamin D (1,25 OH) is a transcription factor!

What does Vitamin D require to enter the nucleus?

Vit D must bind two things:

1. bind to the nuclear vitamin D receptor (nVDR)

2. The VDR must then bind to retinoic acid receptor (or retinoid X receptor)

Once the subunit enters the nucleus, where does it bind? How long does this take?

The nVDR, RXR, VitD3 unit will bind to the Vitamin D response element on DNA to alter transcription of genes → response time is hours to days

What are the 3 genomic effects caused by this change in transcription?

1. increase in intestinal absorption of Calcium

2. Increase in renal reabsorption of Calcium

3. Increase in bone resorption of Calcium

What two mechanisms does the intestinal tract use for calcium absorption? What are both regulated by?

1. Active transport (in the proximal small intestine)

2. Passive, paracellular transport (in intestinal tract and colon)

Regulated by Vitamin D

How does calcium enter enterocytes? How does it exit?

Enters → TRPV6 transporter

Intracellular Transport → D9K transporter

Exits → Ca2+/ATPase pumps

How does Vitamin D affect the intestinal calcium absorption directly? (3)

1. Induces TRPV6 (calcium entry)

2. Induces D9K (calcium transport inside the cell)

3. Induces Ca2+/ATPase pumps (calcium export)

How can vitamin D also increase paracellular transport of calcium?

Induces Claudins 2 and 12 that create “alleyways” for calcium to travel between the cells directly into the blood

How does the kidney differ from the intestine in terms of calcium absorption mechanisms? How is it the same?

Different → Uses TRPV6 and TRPV5 (not just TRPV6)

Different → Uses D28K instead of D9K

Same → Both use Ca2+/ATPase pumps for export

How does Vitamin D affect the kidney calcium reabsorption directly? (3)

1. Induces TRPV5 and TRPV6 (calcium reabsorption)

2. Induces D28K (calcium transport in the cell)

3. Induces Ca2+/ATPase pumps (calcium export)

Compare the organic and inorganic components of bone

Organic → Osteoid 

Inorganic → Hydroxylapatite

What does the organic component (osteoid) consist of? What is it secreted by?

Unmineralized protein matrix that is primarily collagen → secreted by osteoblasts

Compare the function of osteoblasts, osteoclasts, and osteocysts

Osteoblasts → secrete osteoid to mineralize and form bone (build)

Osteoclasts → resorb (degrade) bone

Osteocysts → osteoblasts that are trapped in the bone

How does Vitamin D mediate the activation of osteoclasts indirectly?

Vitamin D activates osteoblasts, which then activate osteoclasts!

(Vitamin D → osteoblasts → osteoclasts)

What is the first step of the genomic regulation pathway for bone resorption?

Vitamin D binds to nuclear VDR inside osteoblasts

What happens once Vitamin D binds VDR in osteoblasts?

Activates transcription of RANKL ( a cytokine )

What is the role of RANKL?

To interact with RANK (a receptor) on immature preoosteoclasts

What happens when preosteoclasts receive the RANKL ligand?

They are induced to form mature osteoclasts

How do these mature osteoclasts resorb bone to return calcium to the bone?

Release HCl, Alkaline phosphatase, colleganase, and other hydrolytic enzymes