Unit 2 - kin 343 VitD and Calcium

New DRI for Vit D done when

in 2010 November - some debate is going on as to wether it should be revised since almost 1 billion ppl are estimated to be vit d deficient

what is Vit C RDA

600 IU

Vit D and age - RDA

Reccomended intake level is same from 1 to 70 years (15-20 microgram)

Vit D and age - UL

Increase with age and as bodies become bigger, however no change in pregnant ppl

Upper level for Vit D

4000 IU

Iu (International units) conversion rate

1IU = 0.025 microgram = 25 nanogram

what mineral alerts metabolism of vit D

Calcium - calcium deficiency

As a result RDA of Vit D automatically assume correct RDA for adequate calcium

They are interrelable in function

Sources of Vit D

diet and endogenous synthesis (sunlight

Two major forms of vitd in food

1. Vit d2

2. vit d3: majority found in humans

Both havve similar responses in the body and in treatment of rickets

both considered to be inactive

Vitamin d2

ergocalciferol - plant form

• mushrooms make it

Vitamin d3

cholecalciferol- animal form

found in cows milk (very low)

Milk

Major source of vitd and is legally required to be fortified in Canada

Vitd absorption

50% absorbed when consumed w meal

• fat soluble vitamin and is packaged in micelles which then transport them to brush border membrane of enterocytes in the gut

• important to consume vit d with a source of fat to ensure absoprtion and micelle formation 9this stimulates release of bile and pancreatic lipase)

• once inside enterocyte, vitD packaged into chylomicrons and are secreted into lymphatics to be taken up by muscle and other parts of body

• vitD transferred from chylomicrons to vitDbinding protein

what happens to vit in liver during absorption

vitd in chylomicrons in lymphatics drain into liver and vitd bound to vitd binding protein goes there too → activation occurs (25-OH vitD) and then released into circulation

Endogenous synthesis (vitd synthesis in skin) - factors (2)

Seasonal variation and latitude variation

Seasonal variation

UV radiation has an effect for how much vitD can be synthesized

Winter: 1.5 IU → Need 1 hour and ½ to get 600 IU (RDA)

Summer : 6.0 IU (4 fold higher) → take 6 mins to get 600 IU (RDA)

Latitude Version

Little to no synthesis in skin of vit d above 40 degrees north (lat) for 3-4 winter months (we are part of that)

at some extreme latitudes they dont have any synthesis for 6 months or more

when are ppl more vit d deficient

In the norther and souther hemisphere of their winter months

what organ synthesizes cholestrol

Skin → the cholestrol is converted to 7-dehydrocholestrol and then absorbed into dermis and epidermis

What does UVB rays do?

When we go to outside and in sushine the UVB rays irradiate 7-dehydrocholestrol and cause the formation of an unstable intermediate

If wearing sunscreen or heavy clothing this process will not be as efficient

What happens in step 3 of endogenous synthesis

Unstable intermediate spontaneously rorate around a carbon and from various molecules when the bonds broken by UVB ray try to join together → one of the stable compounds is vit d 3 cholecalciferol

What happens in step 4 of endogenous synthesis

it is diffused from skin to the blood in micelles and entering the enterocyte then in chylomicrons finally entering the lymphatic system and blood and binding to vitamin binding protein and then into the liver and getting activated to 25-OH vitd3

What is activated orm of vit d 3

25-OH vitd3

why can we spend all day in the sun and not have toxicity

endogenous syntehsis is a self limiting process → diff ways of getting vit d into the body when ingested by food vs when made in the skin

Vitd made in skin stays trapped if all of the vitd binding protein is saturated with other vitd → excess vitd will be sloughed off as other skin cells die

Why doesnt build up cholecalciferol not harm skin cells?

the excess buildup is also degraded with UVB rays if not converted to vitd3→ the unstable intermediate can form other compounds such as lumisterol and tachysterol (only 10-15% of 7-dehydrocholestrol is turned into cholecalciferol. some of these compounds are found to be anti cancer compunds and stop melanoma growth if sustained UVB exposure

how much vitd binding protein is in the cell

a limited amount and once theyr’re all saturated vitd sits in excess

how is vit d activated?

has to be hydroxylated twice (2-OH vitd3) and most organs can do this and they end up keeping the vitD that they keep (not released to circulation)

what organs release vitD in circulation

only liver and kidney release vitd that they make into circulation, others keep it

half life of 25 -OH vit d (calcidiol)

2-3 week halk life (inactive state)

half life of 1,25 -OH2 vit d (calcitriol)

4-6 hrs - only converted upon demand (active state)

vitd activation pathway

Blood (diet and lymph - DBP) → Liver (turn to 25-OH vitd3) → Blood → kidney (1,25 OH2 vitd3) activated only when needed → blood → organs for use

25-hydroxylase localization in body

Mainly found in liver since synthesized there and pools there, every other organ has some form of 25-OHvitd3

major site of activation of vitd3

Kidneys! will pass by kidney multiple times in 25OH form and will be transformed to 1,25 OH form when needed

when does kidney decide to activate vitd3

when blood ca+2 is low → 1,25 OH2 vitd helps increase calcium 3

How does 1,,25 OH2 vitd helps increase calcium 3

Genomically help control these: regulate transcription of these genes (slow)

non-genomically can also control: activated vit D can open calcium channels at the membrane and allow ca+2 to enter (fast)

1. Increase intestinal absorption of calcium

2. Increase kidney reabsorption of calcium

3. Increase Bone resorption of calcium

Genomic regulation when low Ca+2 by active Vitd

1,25 OH2 vitd is a ligand that binfs to the nuclear vitamin D receptor → changes conformation an binds to retinoid X → whole complex moves into nucleus and binds to DNA → causes change in the transcription of the target gene

Slow acting response → have lasting effects for hours or days

Intestinal absorption of Ca+2 (genomic pathway)

Active transport occuring in small intestine

passive transport happen in intestinal tract

both regulated by vit d

Intestinal absorption of Ca+2 (genomic pathway) → Active transport

Happening in small intestine

1. TRPV6 is a channel that lets calcium enter enterocytes from digestive materials → induced and activated by calcitriol (vitD)

2. Once Ca+2 enters the enterocyte it needs to be bound to D9K to go from apical to basolateral side and exit into the plasma

3. energy needed to pump calcium out of cell (active transport) → calcium ATPase transcription is activated by calcitrol (vitd) and is used to pump calcium ions from chyme into the blood

Why does calcium need to bind to D9K in the enterocyte

1. Once Ca+2 enters the enterocyte it needs to be bound to D9K

   1. - Help keep intracellular concentration of calcium low (otherwise cause cramping)

   2. D9K bind to two calcium at once and move it across enterocyte apical to basolateral side to speed up the movement of the calcium ions (rate-limiting)

   3. we need to maintain concentration gradient, free calcium in the cell can decrease calcium uptake

where is calcium typically stored

Sarcoplasmic and ER

Intestinal absorption of Ca+2 (genomic pathway) → Passive transport

1. Calcitrol → trigger claudins 2 and 12 transcription

2. claudins 2 and 12 allow Ca+2 to travel paracellularly in a concentration gradient where calcium is higher than the blood which allows for fast transport of calcium across the small intestine

what are claudins 2 and 12

Molecules that hold adjacent cells together and form tight junctions and is permeable to calcium

Kidney reabsorption of Ca+2 (genomic pathway) → active transport

1. Calcitrol (vitD3) → induce transcription of TRPV6 and TRPV5

   1. Increase reabsorption of Ca+2 from urinary filtrate into renal tubule cells

2. Calcium binds to D28K and travels to the basal side

3. to get Ca+2 back into blood need calcium atpase which are induced by calcitrol

What is TRPV6 and TRPV5

calcium transport channels on apical membrane of renal tubule cells →

what is bone made up of?

Osteoid (secreted by osteoblasts) and hydroxylapatite (10 calcium, 6 phosphate and 2 hydroxide)

osteoclast vs osteoblast

osteoclast : break down bone and form lacunae

osteoblast: bone forming

osteoclast precursor

activated by osteoblasts which are activated by 1,25OH2 vitd (activated form)

why is vit d needed in bone resorption and how

Increase calcium levels in bloods by breakdown of bone → cause indirect activation of osteoclasts by triggering osteoblasts to make RANKL → RANKL trigger precursor osteoclasts → mature overclasts formed → dissolve hydroxypolaties and release calcium

Regulation of Blood calcium (membrane - non-genomic)

activated Vit d acts at the membrane to increase calcium uptake in intestines (dietary calcium)

Where does the non-genomic calcium uptake occur?

on the membrane of the small intestine (duodenum) → enterocytes

What does fast uptake of calcium?

1,25D3 MARRS binds to ligand 1,25 (OH)2 vitD to cause calcium channels to open in enterocytes and birng more calcium in rapidly from the food

why is genomic process so slow?

Have to wait hours for all of the TRPV D9K and ATPase calcium pumps to be synthesized for used and calcium rich meal will not sit around fro that long

what is MAARS and how does it work

G-protein coupled receptor that binds to 1,25VITD3

and activates PKA which activates voltage dependent calcium channels and cause them to open

very fast process and occurs within 1-15 mins of eating calcium

how much do mice lacking MAARS absorb of calcium?

1/3 less calcium

Describe Inverse relationship of blood calcium levels and PTH

Decrease in blood calcium → increase in PTH

what does PTH do?

activate1 aplha hydroxylase in kidney and activates circulating 25(OH) vitD to form 1,25(OH)2 vitD, increasing active Vit D which increases calcium levels again

what cells secrete PTH?

chief cells→ secrete PTH when not being inhibited by CaSR

What is CaSR

calcium sensing receptor that controls how much PTH is secreted by parathyroid/chief cells

narrow range for calcium concentration

Calcium is in a very narrow range of concentration because it is

how does Pth secretion work

CASR in chief cells have calcium bidn to those receptors and inhibits PTH secretion→ when calcium levels are low, calcium unbinds from receptor and PTH is secreted → PTH activates 1 alpha hydroxylase transcription in kidney → alpha 1 hydroxylase in the kidneys result in more conversion of 25(OH) vitD in the blood → 1,25(OH)2 vit d in the blood → increase calcium uptake via genomic and non genomic pathways in intestines, bones and kidneys

How do we ensure our bones dont turn into slush?

after calcium levels have been restored in the blood inhibition mechanisms by vit D itself acts as a neg feedback loop

Neg feedback loop of vit d (3)

1,25(OH)2 vitD inhibits PTH transcription indirectly because rise in calcium levels will cause activation of CaSR in chief ceells and stop PTH secretion and help reduce 1,25OH 2 vitD levels in the blood.

1,25OH2 vitd can also act as a ligand for nVDR and it causes CYP27B1 to decrease and result in less 1 alpha hydroxylase

1,25OH2 vitd can also act as a ligand for nVDR and it causes transcription of 24-hydroxylase, this enzyme hydroxylates 25OHvitd to make 24,25OH2 vitD, it also competes w/ 1-alpha hydroxylase

Substrate competition

24-hydroxylase limits 1-alpha-hydroxylase by snatching more 25OH vitD away and decreasing 1,25OH2 vitD

VitD toxicity

if consume over 10,000 IU dietary vitD per day for several manthis can get hypercalcemia and calcification of soft tissues and excessive bone loss

→ Other symptoms include hypertension, anorexia and hyperphosphatemua

how is vitD excreted

vitD is dat soluble and excreted in bile and some is excreted in urine

VitD deficiency - muscle

1. Myopathy- vitD needed for muscle contractility and myogenesis

   1. vit D deficiency causes muscle weakness, because 1,25OH2 vitD is not being made from 1-alpha-hydroxylase locally for the muscles to use and it grows weaker

vit D deficiency-sunlight

individuals with more melanin will need 10 times longer UVB exposure to synthesize vitD (striking 7-dehydrocholestrol → unstable intermediate → vitD).

Melanin blocks about 100% of UV radiation and indirectly reduce formation of vitD

melanin risk factor for VitD deficiency - cheddar man and polar bear

Polar bear: Live in northern climates (too much sun → have melanin→ no UVB → no vitd),

but get loads of vitd from fish and diet

Cheddar man: also in norther climate (too much sun → have melanin→ no sun → no UVB → no vitD)

Cheddar man moves in land for farming and doesnt have access to vitD in diet from fishing, so they adapt to lose melanin and now ppl in UK are predominantly white.

How did selection for white ppl happen?

Vit D deficiency in cheddar man times caused those women to not develop pelvic bones properly and as a result couldnt give birth properly and therefore couldn’t pass their genes on and so more melanated ppl die, and those with less melanin who could convert UVB into vitD lived on cuz they could produce babies

VitD deficiency- elferly

need an increased requirement for vitD (600 IU (normal) to 800 IU for older)

1. outdoor activity decreases so UVB exposure goes down

2. vitD goes down also 50% decrease of 7-dehydrocholestrol (sebum production goes down) therefore ability to make vitD also goes down.

3. insufficient diet with vit D

4. ability to make PTH to induce kidney to convert 1-alpha-hydroxylase to increase Ca+2 also decreases

Vit D deficiency

Muliple sclerosis, rheumatod arthiritis, T1 diabetes, colon cancer

Multiple sclerosis capital of world

CANADa

wHY IS vitD diseases controversial?

Corelation doesnt equal causation

more ppl die from colon cancer as we go to areas w less UV exposure but we can’t be sure they’re related →vitD not a treatment for cololn cancer

also in places w colon cancer we see there are more houses that were painted by someone else (Affluence) → these ppl have indoor jobs and make hella molney and are not going outside (less vitD) → they die of colon cancer

as we go down in latitude…

UV exposure goes up (highest in texas)

how much calcium in 70Kg?

1-1.5 kG of calcium

post-menopausal women and calcium intake

are exceeding the upper limit (2000 mg/D)

9-18 years RDA of calcium

Highest because puberty happens here and long bones are growing so more calcium is needed