Vitamin+D+Lecture 1

7/29/2019 Vitamin+D+Lecture 1

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Vitamin D History1645 Whistler (1650 Glisson): rickets described

1920 Mellanby: dogs raised indoors (no sunlight)

developed rickets: cod liver oil cured it

1920s McCollum: bubbling oxygen through a

preparation of fat-soluble vitamins inactivatedvitamin A but not vitamin D

1923 Goldblatt and Soames: skin produced a

substance equivalent to vitamin D when irradiated bysunlight or UV light

1920s Hess and Weinstock: skin irradiated with UV

light and fed to rats cured rickets


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Rickets

Mineralization defectHypertrophy of Chondrocytes (cartilage)

Short stature

Bony deformities

In children: bowed legs

defects in rib cage


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Vitamin D3 = Cholecalciferol

Produced in animalsVitamin D2 = Ergocalciferol

Derived from a precursor

found in plants and yeast


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Dietary Sources of Vitamin D

Fatty fish (mackerel and salmon)

Fish oils (cod and tuna liver oils)

Foods fortified with Vitamin D:

MilkCereals

Breads

Fortified foods rarely contain the labeledamount of vitamin D


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Vitamin D is a fat soluble vitamin

HydrophobicPoorly soluble in aqueous environments

such as the intestinal lumen, plasma, and

the cytoplasm of cells

Hence, requires carriers or transport proteins

in aqueous environments

Easily soluble in lipid-rich environmentsso, crosses membranes readily and is

stored in lipid droplets within cells


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Digestion and Absorption:

Fat soluble vitamin: emulsified with lipids and

bile acids

Taken up into enterocytes by passive diffusion


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Vitamin D is

packaged with

dietary lipids intochylomicrons,

secreted into lymph,

then circulates in

plasma. Action of

lipoprotein lipase

removes lipids

into muscle and fat;some vitamin D

stored in fat, as well.

Chylomicron remnants then taken up by liver.


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7-Dehydrocholesterol can be converted to

Vitamin D in the skin; requires UV light

Vitamin D not strictly a vitamin since it can be produced by the body


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The amount of Vitamin D produced in the skin

is reduced with the use of sunscreen

1 minimal erythemal dose (minimum sunburn) used:equivalent to 10,000-25,000 IU of oral vitamin D

(single exposure)

SPF 8 sunscreenused in this

example

Clothing also

reducessun exposure


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The ability to produce vitamin D in the skin

varies with:

Pigmentation: melanin levels reduce UVB to skin

Age:Young 20-30

Elderly 62-80

1 exposure

of minimal

erythemal dose

70 yrs: 75%

reduction in vit.D

production in skin

(reduced 7-dehydrocholesterol in the skin)


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Vitamin D production in skin varies with:

Time of DaySeason of year

Latitude:

42 = Boston; sunlight too dim to producevitamin D in the skin from November

through February

Stores of vitamin D in fat may be adequate toprovide vitamin D in the winter

3 weekly exposures of hands and face for 20 min


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Vitamin D is

converted to

25-hydroxyvitamin D3

in the liver (andalso skin, intestine,

and kidney)

25-OH vit D3 is

exported from liveron vitamin D-binding

protein (DBP)

Metabolism to

1,25-dihydroxyvitaminD3 occurs in kidney;

this is the active form

24,25(OH)2 vit. D3 is

much less active


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Metabolism of Vitamin D:

Hydroxylation of carbon 25 to make 25-OH vit. D3by 25-hydroxylase occurs primarily in liver

(also skin, intestine and kidney)

Export of 25-OH vit. D3 from liver into circulation on DBP25-hydroxylation is poorly regulated, hence,

25-hydroxyvitamin D levels in plasma

are used to determine vitamin D status

Levels of 25-OH most accurately reflectdietary intake and cutaneous production,

since vit. D3 is rapidly converted to 25-OH vit. D3

and this is the major circulating form


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More on Metabolism

Metabolism of 25-hydroxyvitamin D3 to the

biologically active form occurs in thekidney: hydroxylation of carbon 1 to

make 1,25-dihydroxyvitamin D3: export

from kidney on DBP

Other tissues have the 1-hydroxylase, butcontribute little to 1,25-(OH)2D levels

Placenta during pregnancy

Macrophages, other cells

24-hydroxylase in kidney: makes 24,25-di-hydroxyvitamin D: less active,

unknown function, step in degradation

Excreted form: calcitroic acid


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Functions of 1,25 (OH)2Vitamin D3

Functions as a hormone

Primary function in whole body calcium

and phosphorous homeostasis

Maintenance of a healthy skeleton

Maintain serum calcium (10 mg/

100 ml) and phosphorous levels(4 mg/100 ml) for bone mineralization


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1,25 (OH)2Vit.D3 increases calcium levels:

3 mechanisms:

Most important: increases intestinal

absorption of calcium

Increases renal reabsorption of calcium

Increases calcium mobilization from

bone


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1,25(OH)2Vit. D3 is a hormone that binds to the

Vitamin D Receptor, a transcription factor

DNA binding domain: 2 zinc fingers

Ligand binding domain: binds 1,25(OH)2vit. D3

Heterodimerizes with RXR (retinoid X receptor)

Binds to VDREs in the promoters of many genes


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Hormonal action of 1,25(OH)2vitamin D3

9-cis retinoic

acid

Induction

Repression of transcription

Both increases and

decreases in

transcription

of genes

CaT1=TRPV6


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1,25(OH)2Vit.D3 action on Intestine

Increases synthesis of proteins involved

in the uptake and transport of calcium

Increases transcription of genes:

TRPV6/CaT1 calcium channel (epithelium)

Calbindin, a cellular calcium bindingprotein (Ca2+ movement in cytoplasm)

Basolateral calcium pump (export)

Directly increases calcium absorption

across enterocyte plasma membrane

Increases phosphorous absorption in small

intestine by increasingexpression of

Na-Pi co-transporter called Npt2


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1,25(OH)2Vit.D3 Actions on Bone

Bone is continually remodeled

In osteoblasts, 1,25 (OH)2D3 increases the

expression of osteopontin and

osteocalcin, bone matrix proteins

Promotes mineralization by maintenance

of serum calcium and phosphorous levels

When dietary calcium is low, 1,25(OH)2D3

promotes osteoclast differentiation(involved in bone resorption; for

mobilization of bone calcium)


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1,25(OH)2Vit.D3 Action on Kidney

1,25(OH)2D3 suppresses 1-hydroxylaseactivity (decreases further production

of 1,25(OH)2D3)

Stimulates 24-hydroxylase activity: step

towards removal of excess

1,25(OH)2D3 from body

Enhances renal calcium reabsorption


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1,25(OH)2Vit.D3 regulates genes

unrelated to calcium homeostasis

Alters transcription of genes involved in the cell

cycle to inhibit proliferation and induce

terminal differentiation

c-myc, c-fos, c-cis (oncogenes)Used to treat psoriasis, a hyperproliferativeskin disorder

Stimulates immune function

Modulates muscle cell calcium levels and cell growth

Pancreas: enhances insulin secretion

Role in female fertility

Nervous system: antiproliferative, prodifferentiation


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Regulation of Vitamin D Metabolism

25-hydroxylase activity in liver is not well

regulated

1-hydroxylase activity in kidney is highly

regulated through transcription

Low 1,25(OH)2D3 in circulation:

increase 1-hydroxylase activity to

increase 1,25(OH)2D3 production

High 1,25(OH)2D3 levels: decrease

1-hydroxylase activity and increase

24-hydroxylase activity


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More on Regulation of Vitamin D

With vitamin D deficiency, intestinal calcium

absorption decreases from 30-50% to

10-15%; circulating calcium decreases

Parathyroid gland calcium sensor detects Ca2+

levels in serum and increases synthesis andproduction of parathyroid hormone (PTH)

PTH increases renal 1-hydroxylase activity,

to increase production of 1,25(OH)2

Vit D3

,

increases renal reabsorption of calcium,

mobilizes osteoclasts to mobilize bone

calcium (works through a signaling pathway

on pre-osteoblasts)


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Summary of Vitamin D regulatory

Pathway:

25(OH)D3

High PTH

Low Pi

Low Calcium 1,25(OH)2D3

24,25(OH)2D3

High calciumLow PTH

High Pi

High 1,25(OH)2D3

24- OHase

1-OHase


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VDR is essential for post-natal

development

Knockout mouse: targeted disruption ofVDR gene

Animals normal at birth, retarded

growth after birth, then rickets

Developed alopecia by 7 weeks

Males and females infertile

Knockout 1-OHase: rickets, females

infertileCan somewhat cure with high Ca2+, Pi

Knockout mouse: 24-OHase

Defective mineralization of bone


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Non-VDRnuc mediated effects of Vitamin D

Mediated by a vitamin D receptor on the plasmamembrane called VDRmem

VDRmem is not related to VDRnuc

Prefers 1, 25 (OH)2 Vit D3 in the cis form

Initiates intracellular signaling cascade

involving PKC, phospholipase C, MAPK

Increases Calcium absorption by rapid opening

of Ca2+ and Cl- channels


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Summary

Low circulating

calcium increasesPTH secretion

High calcium inhibits

PTH secretion

High 1,25(OH)2vit. D3

inhibits PTH secretion

Phosphate regulates

PTH, but less effect-ively; increased P04

2-

increases PTH

indirectly


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Vitamin D Deficiency

Serum levels of25(OH)Vit D3


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Dietary Recommendations (2010)

RDAs established for first time (assuming allVit D obtained from diet)

Adequate Intakes for infants

(1 g = 40 IU)

g vit. D/dayInfants (birth-1 y) (AI) 10

Children and adults


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Vitamin D Toxicity

Results from >10,000 IU/day for monthsCannot get this easily from dietary sources

Unlikely from exposure to sunlight

Hypercalcemia

Hyperphosphatemia

Hypertension

AnorexiaNausea

Renal failure

Death


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Excess exposure to sunlight can produce

large doses of Vitamin D3 in skin

Unlikely to result in toxicity due to

further metabolism of Vit. D

in skin exposed to sunlight

lumisterol

tachysterol

suprasterol I & IIInactive forms of Vitamin D


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Tolerable upper intake levels of

Vitamin D (2010):

Infants 0-1 y 62.5 g/day (2500 IU)

Children 4-8 y 75 g/day (3000 IU)All others (8 y up) 100 g/day (4000 IU)

Vitamin D intoxication >150 g/L of25(OH)Vit D3 in serum

Vitamin D deficiency


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Decreased calcium absorption due to decreased

calcium intake or decreased vitamin D leads

to an increased risk of fractures


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Factors preserving BMD

Calcium and VitaminD supplementation of dietExercise

Adequate dietary protein levels

Hormone replacement therapy for

post-menopausal women bone turnover rate by 10-15% BMD by 2-5% fracture incidence by 25%

Adequate Vitamin K intake

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Vitamin+D+Lecture 1