vitamin d, ca and p 2014

8/21/2019 VITAMIN D, Ca and P 2014

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MICRONUTRIENTS HNSC 7211

Prof. Kathleen Axen Spring 2014


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The sunshine vitamin

Is it really a vitamin?

An organic compound Natural component of food

Is essential in the diet

>60% of requirement is produced in skin,conditions permitting

For normal physiologic function


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0.025 g (25 ng) of D2 or D3 = 1 IU

DRI ~400IU or 10 g


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Dietary Vitamin D

D2 Corn oil 9 IU/100g

D3 Fish liver oils 10,000 IU/100g

Salmon 220 IU/100g Butter 35 IU/100g Poultry 80 IU/ 100g Poultry skin 900 IU/ 100g

Fortified dairy products (D2 or D3 can be used) Humans do not distinguish between forms (birds do) 400 IU/ quart


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Absorption

Bile required, formation of micelles

Passive diffusion

~ 50% bioavailability

Most (>90%) in chylomicrons

Non-esterified

Transferred to Vitamin D Binding Protein in plasma

Vit D remaining in chylomicron is taken up by liverbut no storage in liver (~1/4 of dose in bone)


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Synthesis in skin

UV B 285-315 nm (UVA > 315nm, does not causesunburn, UVC < 285nm) All UV types can be mutagenic and cause collagen

destruction in skin

Photoisomerization (no enzyme) 7-dehydrocholesterol secreted by sebaceousglands on surface

absorbed through skin to Malpighian-deep-layerbeneath stratum corneum

D3 and metabolites synthesized Excess D3 converted to byproducts


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How much sun exposure do you need for

adequate vitamin D synthesis?

Holicks Rule: MED over of body yields1,000 IU

Or 6-10% of body surface exposed until mildlysunburned (MED)

DRI=200 for most categories (1 IU/.025 g)

How many g?


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Amount synthesized depends on

Thickness of skin, greater in Adults vs. children

Men vs. women

People of African vs. Asian or European ancestry

Amount of pigment (melanin) in skin

Use of sunscreen, clothing

Time of day (highest 10 am2pm) Season, latitude (in winter no D synthesis in

Denver, NYC, Toledo, Beijing)


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Vitamin D Binding Protein

Synthesized in liver

DBP transports D2or D3and metabolites in

plasma Highest affinity for 25 hydroxy vit D

50% of D bound to DBP

Mobilizes vit D formed in skin (so that form ismore efficiently used)


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Other binding proteins

Cytoplasmic

Vitamin D receptor in nucleus (VDR) Binds to 1, 25 dihydroxy D

Necessary for the genomic effects of vit D


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25 hydroxy cholecalciferol (25 OH D)is the major

form in blood; reflects dietary intake


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25 hydroxylase


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Regulation of vit D Metabolism

25 hydroxylase (liver) driven by vit D conc

1 hydroxylase (kidney)

Zinc dependent

by PTH (due to low Ca), prolactin, low phosphate

by FGF 23 (fibroblast growth factor)from osteocytes FGF23 is by calcitriol

It phosphate reabsorption in kidney and absorption in SI

by inflammation

Regulated differently in other tissues

Forms calcitriol =1,25 dihydroxy vit D


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Maintaining normal blood levels of Ca2+ is crucial forsurvival (1M)

It is the job of PTH and vitamin D-related mechanisms Bone is the storage place for Calcium; plasma Ca2+

concentration is a far greater priority than bonemineral content or density

Bone mineral is resorbed to provide Ca for the blood


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Calcium

Ca 2+

Ion in solution

Part of inorganic salts

Buffers

Bone mineral

Tooth mineral (enamel)


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Bioavailability

Increased by

Solubility

Acid

form: e.g. calcium gluconate

Lactose

Ascorbic acid

Interaction with phosphorylated proteins casein

lactalbumin


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Bioavailability

Decreased by

Oxalate

Dietary fiber

Phytate

Ethanol

Fat malabsorption (soap formation)

Tannins, polyphenols (flavonoids)

phytate


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Calcium absorption:

Paracellular: across tight junctions

between intestinal epithelial cells

Big effect of concentration gradient, time in

intestine (length, important in ileum, maybecolon)

transcellular: transport into, across and

out of intestinal epithelial cells Several models proposed, with evidence

> 1 model may operate, or combinations


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Paracellular Transport


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Tight junctions in SI epithelia


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Calcium Transcellular Transport Mechanisms

Ca enters via TRPV6

Crosses via

Cytosol?

ER?

Vesicles?

Exits via Ca ATPase (PMCA)


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Entry: apical surface

Ca2+ channel protein

TRPV6 (transient receptor potential of the vanilloid type)

Expression is increased by calcitriol (VDR-mediated,slow) Rapid effect of calcitriol:

viacAMP protein kinase A activityglucuronide secretionactivation of existing TRPV6 Not via VDR but Membrane Associated Rapid Response Steroid-

binding (MARRS) protein May also be some effect of calcitriol on TRPV6 synthesis (slow)

Ca2+ dependent FBI may be regulated by calcitriol


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Movement across cell--models

1. Calbindin (ferry) protein

1. Induced by calcitriol via VDR

2. probably minor/unlikely

3. See localized, not diffuse Ca after Ca dose

2. Vesicular/lysosomal

1. endocytosis

2. Much evidence

3. Diffusion through the endoplasmic reticulum

1. Vesicles may bud off

h f d l


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The first model


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Lysosomal and ER Models


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Extrusion at basolateral membrane

1. Not rate-limiting

2. Ca2+ ATPaserequires energy, against

concen gradientregulated by calcitriol??

3. Expression of PMCA is not regulated by

calcitriol

4. Exocytosis of vesicles


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Functions of Calcitriol related to

bone and mineral metabolism

Increase Ca absorption, SI Increase phosphate absorption SI (since it FGF23)

Increase renal resorption of Ca (and phosphate) lessloss (since it FGF23)

Bone: roles in mineralization (also 24, 25 dihydroxy D)by providing Ca and PO4, differentiation of osteoblasts

and remodeling (?) Differentiation of macrophages to osteoclasts PTH promotes bone resorption


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BONE

Cortical

tubular, dense (compact)

long bone shaft

Trabecular/cancellous

spiky,spongey

Hip, vertebrae, ends of long bones


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BONE CELLS

Osteoblasts embedded in collagen matrix

move mineral from ecf to bone surface

Become encased in bone--osteocytes

Macrophages differentiate into osteoclasts Differentiation involves calcitriol

Release enzyme to solubilize mineral

Increases plasma Ca and PO4 Remodelling of bone, excavation


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Calcitriol is needed for osteoclast development

Receptor Activator of NF-KB Ligand); on osteoblast surface; it binds to


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ReceptorActivator of NF-KB Ligand); on osteoblast surface; it binds to

a receptor on the osteoclast and promotes its differentiation; RANKL

by PTH and calcitriol

Osteoblast surface

monocyte

OPG: osteoprotegerin Collagenase, HCl

osteocalcin

Expr reg by calcitriol


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Mineralization

Requires adequate ecf concentrations of Ca and

PO4

Ion product (mg/dL) > 40: 10 (Ca) x 4(PO4) = 40

If conc of either ion is too high: calcification of

soft tissue (vit D toxicity)

If ion product too low: defective mineralization


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Phosphorus

As phosphate PO43- in diet, in body

Organic forms

Phospholipids

Nucleic acids Phosphorylated proteins

coenzymes: FAD, NAD, CoA, TPP, PLP

Inorganic forms

Ca3(PO4)2

hydroxyapatite


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Osteoporosis

Decreased bone mass, normal histology

Bone pain, easy fracture

Diagnosis by bone densitometry

Bone Mineral Density by DXA (dual energyXray absorptiometry); ultrasound, CT scan

Unlike osteomalacia it is not curable bynutritional therapy alone

Increased risk with age, menopause, lowpeak bone mass


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C f O t i


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Causes of Osteoporosis

Normal decline in bone mass with age

TRPV post-menopause so Ca absorption

loss of Ca in urine

conversion of vit D to calcitriol

vit D synthesis in skin?

Low peak bone mass

Poor Ca and vit D intakes during bonedevelopment

Low physical activity

Genetic predisposition


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Bone formation and mineralization

Depends on the balance between osteoblastand osteoclast activity


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Therapy for Osteoporosis

Ca supplements have little effect, only

cortical bone

Hormone therapy risky (CVD,

reproductive cancer)

Use of drugs that affect estrogen

receptors

Calcitriol supplements work in elderly

women but concern about negative

effects


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Summary


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Genomic Functions of Calcitriol

Nuclear VDR: skin, mammary, gonads Induced by estrogen? Cortisol?(since post weaning)

VDR-RXR dimer and other forms

Each charged with ligand (calcitriol, 9cisRA )

Vitamin D response elements (VDRE) on DNA

Regulation of transcription of > 50 genes

Calbindins, osteocalcin, vit D receptors, collagen

PTH, FABP, transferrin receptor


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osteocalcin

Most abundant bone proetin after collagen

Found in bone and in blood

Carboxylated form binds to bone mineral

(hydroxyapatitea0

Un-carboxylated osteocalcin increases plasma

insulin level, proleration of pancreatic cells,

and stricter blood glucose control

?role of calcitriol in diabetes?


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Vitamin D and Breast Cancer

Many studies show inverse rel between 25 OH D

levels in blood and colon or breast cancer

activated VDR promotes apoptosis

Mammary cancer cells have 1hydroxylase and VDR

In breast tumors vitD promotes cell differentiation,

apoptosis and to reduce the effects of estrogen onproliferation


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Type 1 Diabetes mellitus

Incidence of T1DM related to latitude andinversely to hours of sunlight

Lack of osteocalcin?

Autoimmune disease Vit D may inhibit production of IL-12 and therefore

activation of cytotoxic macrophages andlymphocytes

Suggestive studies that vit D supplements maylower risk

T 2 Di b t ( i t ti l id )


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Type 2 Diabetes (circumstantial evidence)

Incidence of T2DM highest in winter (Sweden)

VDR ko mice are more insulin sensitive andresistant to diet-induced obesity

25 hydroxy D levels inversely related to BMI, butcalcitriol levels normal in obesity

Chronic inflammation inversely related to 25hydroxy D levels in plasma


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Vitamin D Deficiency--Causes

Lack of sun exposure

Low dietary intake

catabolism: anticonvulsant use

(phenobarbital, diphenylhydantoin)

Hypoparathyroidism

Renal or hepatic disease

Mutations in VDR (autosomal recessive)


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Vitamin Requirement

Based on vitamins effect on bone, not

onother functions

Rickets

osteomalacia

Plasma


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Rickets

Can be due to defic of Vit D and/or Ca Onset 6-24 mos of ageimpaired mineralization

Bone pain

Delayed tooth eruption Delayed closure of fontanelles

Enlarged epiphyseal plates

Bowed legs, knock knee, sabre tibia

Rib deformities (respiratory problems)

Spinal, Pelvic deformities (childbirth)


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Osteomalacia

Onset in older children and adults (once

epiphyses have closed

Decreased bone mineral

Easy fracture

Bone pain, muscular weakness

Osteopenia (low bone density): increased

ratio of non-mineralized to mineralized bone


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Vitamin D Toxicity


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Vitamin D Toxicity

Dietary supplements NOT sun exposure

DRI 5-10 g/d vs UL 50g/d

Some say UL of 4000IU (100g) is safecontroversial

since studies done with old assay systems

toxicity defined by hypercalcemia, but other

toxic effects may occur at lower levels of D intakethan those needed for hypcercalcemia


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Vitamin D Toxicity

25 OH D 25 hydroxy vit D competes with calcitriol for VDR, less

potent than calcitriol but much higher conc

Ca absorption from SI and bone

Hypercalcemia, calcinosis (CaPO4 deposits in soft tissue),calcinuria. Renal calculi (esp in aged)

PTH in response so less Calcitriol formed

Anorexia, vomiting

vitamin d, ca and p 2014

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