Vitamin D

what do we assume with the DRI for vitamin d

assume no sunlight

• the numbers are for people who get their vit d from ONLY food/supplements

1 IU = what

0.025 ng/mcg = 25ng

what units is the dri for vitamin d measured in

IU = international units

the RDA for vitamin d assumes calcium intake is adequate. why 

• one of vit d’s function is calcium absorption 

• if calcium were low, poor absorption could look like a vit d problem

what are the sources of vitamin d

1. food

• Vit D2 (ergocalciferol) - plant form

• Vit D3 (cholecalciferol) - animal form

2. endogenous synthesis through sunlight

which one is the active form: cholecalciferol or ergocalciferol

neither. they both must be converted by the liver/kidney into the active form, calcitriol.

t/f natural milk is a good source of vitamin d

F

only the fortified version is a good source 

define and describe where each of the following are located:

1. micelles

2. chylomicrons

1. micelles - tiny bubbles of fat in the lumen, carrying fat-soluble stuff for absorption

2. chylomicrons - fat-carrying bubbles inside enterocytes that transport absorbed fats towards the basolateral membrane

___% of vitamin d is absorbed

50

the rest gets excreted in feces

what takes Vitamin D to the liver 

vitamin D binding protein 

list the names of the inactive forms of vit d

1. ergocalciferol (Vit D2) - plant forms

2. cholecalciferol (Vit D3) - animal forms

what 2 things promote the formation of micelles

pancreatic lipase and bile

where is Vit DBP found

found circulating in blood 

• has a high affinity for Vit D 

explain latitudinal variation

the farther you live from the equator, the less sunlight ur skin gets during teh winter

• therefore, less vit D is made in teh skin

which inactive form of Vitamin D do humans make

D3

what form of vitamin d does cholesterol synthesize, and WHERE does it synthesize it

7-dehydrocholesterol is synthesized in the sebaceous glands of skin

what % of 7-dehydrocholesterol turns into Vit D3 

10-15%

explain how previtamin D3 turns into Vit D3

1. body heat causes the unstable intermediate to form various different molecules until it reforms into a stable compound

2. then it’ll spontaneously turn into Vit D3

where is inactive VitD3 located

skin 

what reaction turns inactive VitD3 —> 25-OH-Vitamin D3

hydroxylation

list 2 reasons why we can spend everyday in the sun and not develop Vit D3 toxicity, if high levels of Vit D entering the body can be toxic

1. your skin doesn’t make chylomicrons or DBP

• without those two, inactive vitamin d3 stays stuck in the skin

• nothing to transport it into the bloodstream, just stays in the skin

• eventually, skin naturally flakes off, taking excess VitD3 with it

2. if 7-dehydrocholesterol keeps getting hit by UVB rays, it’ll turn into lumisterol adn tachysterol, instead of previtamin D3

• remember only 10-15% of 7-dehydrocholesterol becomes vit d3

which form of vitamin d gets hit by uvb rays

7-dehydrocholesterol

what can 7-dehydrocholesterol turn into when hit by UVB rays

previtamin D3, Lumisterol, Tachysterol, and MANY MANY other different compounds

• this is all to prevent Vit D toxicity from sun exposure

how many hydroxylation reactions must occur for Vit D to become active

two

• once by liver, another by kidney

whats the name for vit d2 and vit d3

d2 - ergocalciferol

d3 - cholecalciferol

name of enzyme in liver that completes 1st activation of vitamin d

25-hydroxylase

whats the name of 25-OH-Vit D3

calcidiol

what is the half life of vit d made in liver and made in kidneys

liver - few weeks, constant supply is made 

• 25-OH-Vit D = calcidiol 

kidney - only a few hours, only made when active Vit D is needed 

• 1,25(OH)2 Vit D = calcitriol

what enzyme is responsible for hydroxylation in the kidneys

1a-hydroxylase

T/F Calcitriol is made and has a constant supply in the bloodstream

F

• that is calcidiol (25-OH-Vit D), inactive from

• the active form of Vit D3 is only made when needed, has a very short half -life

what is the active form of vitamin d called

1,25(OH) 2 Vit D

Calcitriol

which organ is the enzyme 25-hydroxylase found in

liver

which organ is the enzyme 1-alpha-hydroxylase found in 

kidney 

what is the main function of vitamin d

to raise calcium levels in blood

what are teh 3 ways vit d raises blood calcium levels

1. increasing intestinal absorption of calcium

2. increasing kidney reabsorption of calcium

3. increasing bone resorption of calcium

what does nVDR bind to, once activated by Vit D

nVDR heterodimerize with RxR, forming a complex that moves together and binds to the response element, “Vitamin D response element” located in the nucleus

what does RXR and RAR stand for

RXR = Retinoid X Receptor

RAR = Retinoic Acid Receptor

what is the difference between the genomic pathway and non-genomic pathway 

genomic 

• extremely slow since u are you directly changing transcription 

• effects are long-lasting (hours or days) 

if someone’s stomach acid gets reduced and the pH increases, what happens to calcium absorption

without proper, acidic stomach acid at a ph = 1-3, it would not be able to free calcium from the things its bound to

• only free calcium can get absorbed by enterocytes

• there would be less free calcium available = poor absorption

is the concentration of free calcium high or low inside enterocytes.

low

where is free calcium stored in

most cells store free calcium in the endoplasmic or sarcoplasmic reticulum

once calcium enters the cell, list 3 reasons why it needs to be bound up

1. free calcium inside cells is dangerous

• free calcium inside cells can activate cell signalling pathways and cause cellular processes to go out of control

• will active signalling and react with pathways on its own

2. D9K helps by binding to calcium (this isn’t a reason why its bad but whatever)

3. concentration gradient won’t be maintained

• for calcium absorption to work properly, calcium must be low inside and high outside

• otherwise, TRPV6 weakens and wont be able to bring calcium into cell

explain how D9K is both a protector and transporter 

protector 

• protects the cell from accumulating too much free calcium 

• maintains the gradient for TRPV6 

transporter 

• shuttles calcium across cell towards blood 

how does vitamin d increase/decrease the transporters/protein needed for calcium absorption

• vitamin d does so via the genomic pathway

• it doesn’t act like a ligand for the transport

• will bind to nVDR, which heterodimerize with RXR, which binds to Vitamin D response element, to inhibit/active transcription of the proteins that help with calcium absorption

is the concentration of calcium higher in the intestine or blood

intestine

does calcium absorption occur actively or passively 

BOTH 

1. active

• TRPV6 allows calcium to enter cell passively 

• D9K shuttles calcium across cell (we dont want free calcium inside cell)

• Ca2+-ATPase moves calcium into bloodstream using ATP 

2. passive

• transmembrane proteins located in the tight junctions between enterocytes, selective and permeable to calcium

• allow calcium to passively move directly from intestine into bloodstream, paracellularly 

what’s the term for epithelial cells lining the kidney?

renal tubule cells

what are the transporters involved in kidney reabsorption

1. TRPV5 and TRPV6 - calcium channels that let calcium enter renal tubule cell from filtrate

2. D28K - shuttle that binds to calcium and carries it across the cell

3. Ca-ATPase - uses energy to pump calcium into the blood

what are the 2 functions of osteoblasts

1. secrete collagen which makes the osteoid (organic component of bone)

2. secrete calcium and phosphate onto the osteoid, forming hydroxyapatite crystals which is what hardens bone and gives it structure/strength

• called “mineralizing” bone

what do osteoblasts and osteoclasts secrete

osteoblast - secrete collagen and other proteins (for the organic matrix), calcium and phosphate (to from hydroxyapatite)

osteoclasts - secrete acid (to dissolve hydroxyapatite) and enzymes (to digest the organic matrix, releasing calcium and phosphate)

what does it mean when we say bone is always being remodelled

—> constantly being broken down and rebuilt, over and over.

• osteoclasts are constantly breaking down damaged/old bone and osteoblasts are constantly rebuilding that bone

• keeps bones strong by repairing the tiniest damage IMMEDIATELY, before it becomes a bigger issue

throughout one’s entire life, bone is always being remodeled, it’s just the speed/rate that changes

T/F Osteoclasts have to be activated before becoming fully functional 

T 

list 2 reasons why lacunae is crucial

1. after formation (by osteoclasts), it releases calcium adn phosphate into blood if body requires

2. prepares the site for new bone formation (for osteoblasts to come)

what are trapped osteoblasts called

osteocytes

T/F vitamin D DIRECTLY causes calcium to be released through intestinal absorption, kidney reabsorption, and bone resorption

F

directly only with the intestine and kidneys

with bone, it’s indirectly

what is the name of enzyme that activates Vit D in the kidneys

1-alpha hydroxylase

where is the RANKL gene located

a gene located on the Vitamin D response element (VDRE)

• once the nVDR-RXR complex binds to the VDRE near the RANKL gene, it activates the transcription of RANKL

• all inside osteoblasts 

where is the RANK protein located

a receptor located on the surface of precursor osteoclasts 

what are RXR and RAR

they are nuclear receptors that can pair with nVDR

• RXR = Retinoid X receptor

• RAR = Retinoid Acid Receptor

non-genomic calcium absorption happens where

only in the intestine

what activates G protein

once its bound to GPCR (g protein coupled receptor), which is MARRS for the non-genomic pathway of calcium absorption

what is pka

a specific kinase (molecule that adds phosphate group to protein to turn on/off) that is activated by cAMP (small messenger molecule)

• pka phosphorylates other proteins to change their activity

what activates MARRS

the binding of vitamin D (the ligand)

name of transporter used in non-genomic calcium absorption

VDCC (voltage dependent calcium channels)

• located on apical membrane of enterocytes

• allows calcium to rapidly enter cell

• happens within 1-15 min of vitamin d exposure

describe process of non-genomic calcium absorption 

1. vitamin D binds to MARRS (g protein coupled receptor, activating it

2. activated MARRS activates the g protein inside cell

3. this starts a cascade of signals, one of them including PKA

4. PKA phosphorylates VDCC located on the apical membrane of enterocytes 

5. VDCC opens, allowing calcium to rapidly rush into cell 

how long does the non-genomic pathway take and why is it so much faster than the genomic pathway

happens in 1-15 minutes after vitamin d exposure

• much faster than genomic (which takes hours) bc genomic requires making new proteins (transcription AND translation)

what is the main, primary function of vitamin d

to tightly regulate blood calcium levels by acting on the intestines, kidney, and bone

T/F A fall in blood calcium levels can be lethal 

T 

cells in the parathyroid gland are called what. what is its function

chief cells

—> monitor blood calcium levels, sense changes, adn release PTH (paraythroid hormone when necessary)

aka principal cells

name of receptor located on surface of chief cells

calcium sensing receptor

• checks blood calcium levels

what does CaSR do when blood calcium is high/low

high 

• CaSR signals parathyroid gland to release PTH 

low

• CaSR signals parathyroid gland to stop releasing PTH 

_____ secretes parathyroid hormone

chief cells that make up the parathyroid gland

what are the 2 major functions of calcium

participating in:

1. muscle contractions

2. neural depolarization

how much can blood Ca fluctuate to still be considered within the normal range? 

blood Ca²⁺ can fluctuate by about ±70 µM 

explain what happens in the parathyroid gland when calcium levels are norma. what about when blood calcum levels drop? 

normal

1. CaSR on chief cells is able to sense normal calcium levels

2. blood calcium activates CaSR to produce a TONIC INHIBITION of PTH by parathyroid/chief cells

3. the tonic inhibition keeps PTH secretion turned ON, but at low activity

4. this maintains the blood calcium range that its at (good range

drop 

1. CaSR senses blood calcium levels dropping and immediately stops tonic inhibition 

2. CaSR signals chief cells to secrete PTH 

3. PTH travels to kidneys to induce transcription of 1-alpha-hydroxylase 

4. 1-a-hydroxylase makes lots of active Vit D 

5. Vit D acts on intestine, kidney, and bone to increase calcium absorption 

6. range restored!!! n        

how do u turn off vitamin D production once blood calcium homeostasis is restored

1. PTH secretion is suppressed by Vit D

2. PTH secretion is suppressed by calcium

3. Vit D inhibits its own synthesis

4. Vit D promotes 24-hydroxylase

what are the 2 functions of 24-hydroxylase

1. it converts active Vit D (1,25(OH)2 Vit D) into 24,25(OH)2Vit D - an inactive form

• destroys active Vit D (calcitriol)

2. prevents more Vit D (calcitriol) from being made

• takes 25-OH-Vit D (calcidiol) and also turns it into 24,25(OH)2Vit D (inactive)

explain how substrate competition exists between 24-hydroxylase and 1-alpha-hydroxylase 

both 24-H and 1-alpha-H used calcidiol (25-OH-VitD) as a substrate 

• 24-H uses by turning into 24,25(OH)2 Vit D (an inactive form) when calcium homeostasis is restored 

• 1-alpha-H uses it to make active Vit D (calcitriol) 

when blood calcium homeostasis is restored, Vit D bind to nVDR, inducing transcription of the 24-H gene 

• this creates more 24-H, so more 25(OH)Vit D (calcidiol) turns inactive, instead of becoming calcitriol

where are most fat-soluble compounds excreted

bile

define bile

a fluid made by the liver that helps digest fats, then removes them from the body in feces

unmetabolized vit D is excreted in ___________, metabolized vit D is excreted in ________

bile;urine

how does vitamin D indirectly raise calcium levels through bone resorption

how does a deficiency in Vitamin D affect the muscles

1. reduced protein synthesis for calcium handling

• Myocytes (muscle cells) require two proteins that help muscle contract

  • Calcium ATPase pumps → pumps calcium back into storage AFTER a contraction. allows muscle to relax + prepare for the next contraction

  • Voltage-sensitive calcium channels → allow calcium to enter mycotes when muscle is told to contract

2. myogenesis

• there is a protein inside myoblasts (mature muscle cells) that can bind to calcitriol 1,25(OH)2 Vit D

• this induces transcription of genes required for muscle growth and repair (calcium atpase and VSCC)

• muscle cells can activate Vit D themselves since they have 1-a-hydroxylase inside the cell, which they use to control muscle growth and repair

define melanin and the melanin index

melanin → a dark pigment responsible for colour in ur skin/hair

• made by a neuroendocrine called melanocytes

melanin index → non invasive scale that measures how much melanin is present in the skin

explain what it means when we say melanin absorbs or refracts/scatters almost 100% of uv radiation

absorbs - absorbs it into the skin but prevents it from reaching the deeper layers of our skin, where it can cause damage

refract - redirecting the light away from the skin, preventing it from sgoing deeper into tissue

• aka bounces off the surface rather than penetrating skin

why do people with darker skin (aka more melanin) need much more sun exposure to synthesize Vit D3

melanin acts as sunscreen, refracting UV rays to prevent it from reaching the lower epidermis of skin, causing harm

• one w darker skin blocks more UV rays, producing Vit D3 very slowly

People with high content of melanin may need up to ___x longer UVB (sun) exposure to synthesize the same amount of VitD as people with low melanin content 

10

T/F Melanin block ALL UVB

F

melanin REDUCES AND CONTROLS how much gets through

• light skin

  • lets more UVB reach lower epidermis and make vitamin D quickly

  • but higher DNA damage risk

• dark skin

  • melanin absorbs and scatters more UVB

  • less UVB reaches lower layers

  • Vit D production is slower

  • but it provides more natural protection from UV rays and skin cancer

If polar bears have so much melanin to help them survive in colder climates, how come humans who have adapted to live in northern latitudes often don’t?

polar bears get lots of Vit D from eating fish, maintaining a lot of Vit D in their skin which helps them absorb energy from sun to keep the warm

• they get their Vit D from diet, don’t have to rely on endogenous synthesis

humans don’t eat enough fish in their diet to compensate for the lack of endogenous synthesis.

• if you have dark skin (lots of melanin), this blocks UV rays, less Vit D endogenous synthesis

• combined with low dietary Vit D, this increases risk of Vit D deficiency

this is why humans living in northern latitudes have evolved to have lighter skin

• helps make endogenous synthesis more efficient

T/F Melanin can absorb UV and convert it to heat

T

evolutionarily and historically speaking, why have people living in northern latitudes become more melanin deficient

vitamin D deficiency can lead to problems with bone development. in females, if the pelvic bone failed to properly absorb, it can cause death during childbirth

those who survived and had lower melanin content (therefore, more Vit D) passed their genes to the next generation

• genetic mutations that reduced the melanin content in skin were favoured, especially in places w less sunlight

ppl living in the northern latitude became more melanin deficient, to become better at Vit D synthesis

list 4 reasons why elderly are at a higher risk of Vit D deficiency

1. inadequate sun exposure

• not going out as much = reduced endogenous synthesis

2. reduction in the synthesis of cholecalciferol in skin

• theres a 50% reduction in 7-dehydrocholesterol levels in old people

• 7-dehyro is secreted in sebum, and sebum production declines with age

• dietary Vit D becomes much more important

3. insufficient dietary Vit D - many MN intakes decrease with aging

4. with age, the ability of PTH to induce 1-a-h enzyme is reduced

• this means the kidneys will produce less 1-a-h when blood Ca declines

  • the general rule is if u have less of an enzyme (1-a-h), you should try and have more substrate, so that the enzyme can work at a faster pace

• this is why the RDA for eldery incrases from 600 —> 800 IU

  • this keeps blood calcidiol (25-OH-D) high. even w less 1-a-h, enough calcitriol (1,25(OH)2 Vit D) cna be made when needed

medical term for vit d deficiency

• Hypovitaminosis D 

compare the half life between calcidiol and calcitriol

calcidiol

• few weeks

• constant supply kept in circulation

• not active remember

calcitriol

• once active, only lives for a few hours

• activity time is limited

• only made when needed