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RDAs for adults

Vit K: females 90 g/day

Males 120 g/day

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Dietary Deficiency of Vitamin A

40% of children in the world deficient

Blindness in ~500, 000 children

Death to ~300,000 within months of blindness

High risk of infection, failure to suppressinfection

Mortality of pregnant women

South Asia, SE Asia, Africa most affected Not only lack of Vit A and pro-Vit A is

responsible; also worsened by lack of proteinand fat

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Forms of Vitamin A

Retinol

Retinyl esters (retinol+fatty acid)

Retinyl palmitate

Retinyl acetate

Retinal/retinaldehyde

Retinoic Acid Provitamin A (e.g. -carotene)

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All trans retinol

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Retinyl palmitate (a retinyl ester)

Ester link between retinol and

palmitic acid

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All trans retinal/retinaldehyde

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retinolretinal retinoic acid

NAD+accepts H

NADH+ H+

donates H

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Carotenoids

Organic pigments produced by plants andalgae

Found in chloroplasts and chromophores

Functions: absorb light and protectchlorophyll (AND PHORECEPTOR PIGMENTS!)from photo damage

Carotenes (do notcontain oxygen) Xanthophylls (do contain oxygen)

Lutein, zeaxanthin, lycopene

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Carotenoids

Isoprenoids (most 40C) with

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Pro-vitamin A (carotenes) and non-provitaminA

Lycopene (tomato, watermelon, pink GF)

EPI: Anti-carcinogenic

Lutein (spinach, kale, corn)

non-pro-vitamin A In retina, protect from excessive blue light

May protect against macular degeneration

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Lutein

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Vitamin A activity

Since different forms have different potencycannot just quantify by mass

1 Retinol Activity Equivalent (RAE):

1 ug all trans retinol 12 ug -carotene

24 ug carotene, carotene, cryptoxanthin

700-900 micrograms RAE DRI 1 IU~.3ug all trans retinol but different

relative activity of B-carotene

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Digestion and Absorption

Retinyl esters retinol + fatty acid

RE dissolves in dietary fat

Need:

bile to emulsify (micelle formed with dietary fat)

pancreatic esterases

RE hydrolases from enterocytes

Retinyl ester + H2O retinol + fatty acid

lipase

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Retinol, retinal go into enterocyte by diffusion andform new RE

Retinol acyl transferases (LRAT (main), ARAT)

Palmitate>stearate as fatty acid esterified with R

RE become part of chylomicronslymphaticcirculation blood

Some retinol/al goes directly into portal blood

Retinoic Acid is absorbed into the portal

circulation and attaches to albumin in the blood

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Retinyl

esters inlipoprotein

particles

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Digestion and Absorption of Carotenoids

Carotenoid must be released from chloroplasts orother plant structures (may need cooking)

Need bile for micelle formation

affected by fat malabsorption decreased by olestra (sucrose polyester),

orlistat/xenical (lipase inhibitor)

Carotenoids enter enterocyte

Receptor (SR-BI) mediated uptake (saturable) Same as for cholesterol, vitamin E, lycopene

Also in peripheral cell uptakeretina

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TWO POSSIBILITIES

#1:Carotenoids (~40%) become part of chylomicron stored mainly in adipose tissue, corpus luteum, lutein in

macula=central retina

#2:conversion to retinal (retinol) in enterocyte:

BCMO1(carotene mono oxygenase breaks bond between C15and C15, not on lycopene

Also acts in non-intestinal cells:retina, mammary gland, adrenal,testes, ovary, liver

Product is 2 retinal,which is then reduced to retinol Retinol + FAretinyl ester and incorp into chylomicron

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Also a 9 10 oxygenase

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BCMO1

ARAT

If the fatty acid

came from lecithin

then the enzyme

LRAT is involved

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Regulation of carotene metabolism

BCMO1 activity in Vit A deficiency and in

high Vit A intake

Both SRBI and the enzyme BCMO1 are regulated by the

amount of retinoic acid in the cell via PPAR(RA-RXR dimer

with PPAR decreasing expression of gene for enzyme) Does inflammation alter conversion?

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Uptake and conversion of -carotene to retinal

Sopeople with high retinoid intakes have lower rates of

conversion of -carotene to retinol

High -carotene intakes do not cause

hypervitaminosis A

45% of western pospulation are low-

converters

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Asymmetric cleavage of carotene

BCDO 2 (dioxygenase) produces one product

with a long side chain and one with a short

side chain

The one with the long side chain may have a

specialized function (apocarotenoids >20C)

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Metabolism of absorbed vitamin A

Carotenoids stored in adipose tissue, corpus

luteum, (lutein in retina)

Retinyl esters stored in stellate cells of liver

RE mobilized from storage by RE hydrolase( in protein deficiency)

Retinol conjugated with glucuronide by liver,excreted in bile

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Mobilization of vit A from liver

Retinol transported in blood by plasma

Retinol Binding Protein (RBP4) 21kDa

which is attached to

TransThyRetin (TTR)56kDa (aka pre-albumin), which also binds 4 molecules of

thyroxine

Decreases catabolism of RBP by kidney

T1/2 of holoRBP 11-16 hours

TTR:RBP:retinol::1:1:1

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Plasma Retinol Binding protein RBP

Controls blood levels of retinol Protect Retinol

Protects lipids from retinol

Apo RBP catabolized by kidney

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All retinoid binding proteins

Allow vit A to travel in aqueous medium

Direct vitamin A (targets cells, organelles?)

Protect bio membranes Decrease oxidation of vit A

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METABOLISM OF RETINOL

once it gets to cells

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METABOLISM OF

RETINOIC ACID

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Summary: in blood

B-carotene in lipoprotein particles

Newly absorbed RE in lipoprotein

particles Retinoic acid on albumin

Retinol on RBP:TTR

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Visual Cycle (retinol/retinal)

Vitamin A absolutely necessary for sight

Rods-gradations of any light

Cones-detection of wavelengths (blue 420,

green 534, red 563 nm)

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The Eye !

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photoreceptors

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Vitamin A in the visual cycle

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Visual

Cycle

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Hyperpolarization of inhibitory receptor

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Hyperpolarization of inhibitory receptor

allows signal I see to be sent

Li h h l i i f i

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Light causes hyperpolarization of neuron so it stops

inhibiting its neighbor from firing

depolarized

Hyper polarized

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Functions of retinoic acid

Retinoic acid is the form of vitamin A that is

involved in regulation of gene expression

Retinol retinal via short chain retinol

dehydrogenases/reductases (reversible)

retinalretinoicacid (RA) (not reversible)

All trans RA and 9-cis RA

Non-visual cycle functions of vitamin A

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Retinoic Acid Nuclear Receptors

RAR binds to all isomers of RA

BUT All-trans retinoic acid has greatest affinity (itis its endogenous ligand)

RXR binds to 9-cis

RA

Heterodimers of RAR-RXR or RXR-other nuclearreceptors EACH with its ligand bind to response

element on DNA (gene promoter) empty homodimers/tetramers repress gene

expression (recruit co-repressors at specific DNAsequences)

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Retinoic Acid Nuclear Receptors

RXR- 9cis RA also binds to other nuclearreceptors attached to their ligands:

RAR:RA TR:thyroidH

LXR:cholesterol

VDR:calcitriol

PPAR:PUFA (PPAR is peroxisome proliferatoractivated receptor) All trans retinol can bind to PPAR /, activate PDK, Akt1

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Nuclear receptors have domains that bindboth their ligand and a Response Elementon promoter region of a gene (DNA) RAR-RXR binds to Retinoic Acid Response Element

(RARE)

Typically transcription of specific gene

So vitamin A is necessary for the expression ofmainy genes (severe deficiency is fatal)

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RAR:RA activated genes

Growth hormone GLA proteins

Uncoupling Proteins

Insulin-Like Growth Factor (IGF)

PDX (differentiation of pancreatic cells)

Genes involved in Embryonic development

Spermatogenesis

Osteoclast activity

Hematopoiesis

Immune function

Differentiation of epithelial cells (mucous vs. keratin)

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Vitamin A Deficiency

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Vitamin A deficiency

Nyctalopia (night blindness)due to impaired

regneration of rhodopsin due to lack of retinal

Xerophthalmia: anatomical breakdown of the

eye related to lack of mucus, damage by

immune process, collapse of lens, perforation

of cornea. Due to lack of retinoic acid

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Nyctalopia night-blindness DUE TO EFFECTS ON VISUAL CYCLE

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Nyctalopianight-blindnessDUE TO EFFECTS ON VISUAL CYCLE

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DUE TO EFFECTS ON GENE EXPRESSION

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Xeropthalmia:main cause of

childhood blindness

Xerosis;

keratomalacia(softening ofcornea)

Collapse of eye structure

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DRI: 700-900 RAE

AND CONGENITAL DEFECTS

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Vitamin A toxicity

Hepatic storage capacity is exceeded

Acne meds (13-cisRA); pre-formed vit A

Birth defects: CNS, cranio-facial,CV, thymic

Critical period early in first trimester

NOT same for carotenoidscarotenodermia(but breakdown can produce pro-oxidants)

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10,000IUroughly equiv to

800RE

Ph l i U f R i id

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Pharmacologic Use of Retinoids

Cancer therapy

All trans retinoic acid

Induces differentiation

Causes cell cycle arrest

Induces apoptosis (programmed cell death)

These effects should slow tumor growth

Often RA does but it some types of tumors it

promotes proliferation (neurons, lung epithelium)

Th l f th CLARET t d

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The lesson of the CLARET study