Vitamin A Flashcards
What type of fat is vitamin A?
prenol lipids → isoprenoids → retinoids = vitamin A & metabolites
chemical name of vitamin A
all-trans-retinol
etymology of vitamin A
retina + ol
* Early work associated with vision and the retina + (OH) alcohol
retinoid
A retinoid is any naturally occurring or synthetic compound that bears a structural resemblance to all-trans-retinol with or without the biological activity of vitamin A.
* The term vitamin A is often used interchangeably with the term retinoid.
structure of vitamin A
- beta-ionine ring
- isoprenoid chain: double bonds are in the trans- configuration
- Polar end group (hydroxyl): This gets modified metabolically most often to produce other metabolites
What forms of retinoids found in?
- dietary
- transport
- storage
- active
- metabolic forms
dietary forms of retinoids
- preformed vitamin A
- provitamin A carotenoids
preformed vitamin A types
retinyl ester
* retinyl palmitate: esterfied to a fatty acid
* retinyl acetate: esterfied to aceto group (smaller and not naturally occuring)
provitamin A carotene types
- β-carotene is basically 2 vit A put together so yields 2 molecules
- 𝝰-carotene and 𝛾-carotene only yield 1 molecule of vit A
- Not all carotenoids are created equal – some are not provitamins such as lutein and lycopene
How is retinol transported
- Postprandial retinoid is transported as retinyl ester (RE) in chylomicrons
- Retinol is transported in the circulation bound toretinol binding protein (RBP) in both fasting and non-fasting circulation (liver secretes this)
How are retinoids stored?
Hepatic stellate cells (HSCs) are the primary storage site (>70%) of retinoids in healthy adults
* HSCs represent only ~5% of all cells in the liver, yet >90% of total hepatic retinoid content is found within HSCs. Retinoid is stored in HSC lipid droplets in the form of retinyl ester (primarily retinyl palmitate).
What are the active metabolites of retinoids?
- 11-cis-retinal (aldehyde): chromophore required for vision where photons hit the double bond in vision and generates the image (derivative of vit A)
- All-trans-retinoic acid (carboxylic acid): transcription factor ligand which changes levels of gene transcription (true vit A)
what are the metabolic forms of retinoids?
Metabolic forms of retinoids include non-active metabolites, existing as metabolic intermediates or breakdown products for excretion.
* Alcohol to COOH goes through an intermediate aldyhyde (retinal)
How are dietary reference intakes expressed?
Dietary reference intakes expressed as Retinol Activity Equivalents (RAEs) 1 RAE
* = 1 μg all-trans-retinol
* = 12 μg β-carotene
* = 24 μg other provitamin A carotenoids
One international unit (IU) of vitamin A = 0.3 RAE
DRIs for vitamin A
M = 900 ug RAE/d & F = 700 ug RAE/d
* Males > females linked to larger body pool size
* Increased intake during pregnancy accounts for fetal growth and accumulation
* Increased intake during lactation accounts for secretion of vitamin A into breast milk
* needs also increase with age
In general how is vitamin A gotten from dietary source?
- Approximately two thirds of dietary retinoid intake from pre-formed vitamin A
- Approximately one third of dietary retinoid intake from provitamin A carotenoids
Vitamin A foods
- Dairy & cereals (a lot are fortified)
- Brightly colour carotenoid rich foods; colourful veggies, dark leafy greens (peppers, spinach)
prevalence of vitamin A intake
Most adults consuming a balanced diet consume ample amounts of vitamin A in their diet
* Vitamin A supplementation is not recommended in well-nourished adults
Assessments of vitamin A status
- clinical symptoms (night blindness but means they are already deficient)
- circulating retinol (blood test)
- tracer studies (inject stable isotope - best)
- Liver biopsy (gold standard but unethical)
Plasma retinol concentration and vitamin A status
Are circulating levels of retinol enough?
To a point it can identify vitamin A deficiency
BUT it can mask marginal vitamin A status since circulating vitamin A levels maintained at ‘normal’ level, despite depletion of hepatic vitamin A content
* no vitamin A in diet has shown no changes with circulating levels with Retinol secreted from liver at ~constant rate so it can mask deficiency
* Circulating retinol levels do not necessarily correlate with hepatic vitamin A levels
* Circulating levels maintained UNTIL liver almost completely empty of its vitamin A stores
Measuring vitamin A status with tracer studies
Tracer studies with accompanying models can be used to calculate vitamin A status whereby a labelled retinoid is added to a bolus and see how much ends up in circulation
* High amount of tracer would suggest you have low liver reserves
* “isotope dilution”: Seeing how much of tracer to normal retinol
basic steps of vitamin A absorption
comparable with absorption of other lipids
1. Hydrolysis in in lumen
2. Uptake into enterocytes via diffusion
3. Esterification and packaging into chylomicrons
4. Secretion of chylomicrons into lymph
absorption of retinyl esters (preformed)
- Hydrolysis: occurs in lumen via Retinyl ester hydrolase (REH) which cleaves it to generate a moelcule of retinol (and a fatty acid spawned off of it)
- Uptake: can just flip flop across the intestinal mucosa into enterocyte
- esterification: Becomes retinyl ester again via Lecithin:retinol acyltransferase (LRAT) and then packaged into CM
- secretion: CM secretion into lymph
Absorption of beta-carotenes (pro vitamins)
- uptake: Not metabolized in the gut lumen and is taken up as a whole molecule via transfer proteins into the enterocyte
- cleaved: carotenoid cleavage enzyme (CMO) Cut b-carotene in the middle, central cleavage to get 2 mocleusl of retinal (aldehyde)
- reduced: Retinal has to be reduced to retinol via retinal reductase
- esterification: Becomes retinyl ester again via Lecithin:retinol acyltransferase (LRAT) and then packaged into CM
- secretion: CM secretion into lymph
Role of liver in vitamin A metabolism
~75% of chylomicron retinyl ester taken up by liver (some by adipose) acting as a warehouse for storage and supplying the rest of the body
1. Hepatic uptake of chylomicron retinyl ester
2. Storage of vitamin A within the liver as retinyl ester
3. Secretion of retinol into the circulation
1) Hepatic uptake of chylomicron retinyl ester
- RE is in CMr and is taken up by hepatocytes via Receptor-mediated uptake (LDL-R)
- RE then converted to retinol by neutral early endosome (nREH) or acidic late endosome (nREH)
- Retinol bound to Cellular retinol-binding protein-1 (CRBP-1) to solubilize it in an aqueous environment
2) Storage of vitamin A within the liver (retinyl ester)
Retinol CRBP gets transferred to the stellate cells and converted ack to retinyl ester via LRAT and stored as retinyl ester in lipid droplets
3) Secretion of retinol into the circulation
REH can convert retinyl ester back to retinol:CRBP in the stellate cells which are trasnferred back to hepatocytes and secreted as retinol:RBP to circulate to other tissues
Metabolism of 11-cis-retinal
occurs only in the eye
* all-trans-retinol gets converted to 11-cis retinal which is the active metabolite in the retinal pigment epithelium and the 11-cis retinal rod outer segment which light sensing and Photon of light hits the double bond and switches it back to the trans
Metabolism of all-trans retinoic acid
all-trans-retinol (C-OH alcohol)
↓ RDH: Retinol dehydrogenase
all-trans-retinal (C=O aldehyde)
↓ RALDH: Retinal dehydrogenase
All-trans-retinoic acid (COOH carboxylic acid)
All-trans-retinoic acid can then go into nucleus for transcription activity or breakdown to hydroxy metabolites via CYP26
Role of binding proteins in metabolism of all-trans retinoic acid
binding proteins carry them through an aqueous environment and can help channel into nucleus and degradation
* CRBP: cellular retinol binding protein binds retinol and retinal
* CRABP: cellular retinoic acid binding protein binds retinoic acid
Sources of retinol for retinoic acid synthesis
Circulation or local storage in lipid droplets
* circulation: transporter Stra6 can bind retinol RBP to facilitate uptake into cell
* local storage: retinol:CRBP can come from retinyl ester in lipid droplet via REH (also vicversa via LRAT)
Vitamin A function in vision
phototransduction
* Opsin bound 11-cis-retinal undergoes photoisomerization when struck by light.
How does the phototransduction occur?
The O ppsin bound 11-cis-retinal changes conformation from a resting state to a signalling state upon light absorption, which activates the G protein, thereby resulting in a signalling cascade that causes a change in the membrane potential of the rod cells and fires a signal through optic nerve and processed in brain as light.
* transmembrane receptor in the disk membrane
How does retinoic acid regulate levels of gene expression?
Retinoic acid directly regulates gene expression via ligand dependent nuclear hormone receptors
What are the nuclear receptors for retinoic acid?
There are six different nuclear receptors for retinoic acid (2 families):
* Three Retinoic Acid Receptors (RARs): RARα, RARβ, and RARγ (all-trans-retinoic acid)
* three Retinoid X Receptors (RXR): RXRα, RXRβ, and RXRγ (9-cis-retinoic acid?)
RARs and RXRs function as dimers (i.e. RARα:RXRα heterodimer)
Where do RARs bind
RARs bind to consensus sequences in the promoter regions of target genes called Retinoic Acid Response Elements (RARE)
role of histones in gene transcription
Histone acetylation and deacetylation effects levels of gene transcription
* Acetyl groups causes repulsion actions and local unwinding so DNA becomes more open and can be targeted.
* If the acetyl groups are removed then histones more tightly packed and DNA is not exposed
retinoic acid action with histone deacetylation
Repression of gene transcription where genes are turned off
* Co-repressor complex: RAR and RXR are on the RARE but no retinoic acids can be bound since histone is tightly packed
retinoic acid action with histone acetylation
Transactivation of gene transcription
Local unwinding of DNA so local transcription can get access and turn on transcription with Retinoic acid being able to bind to the RAR
Why is retinoic acid signaling so important?
- Retinoic acid regulates the expression level >500 genes
- Retinoic acid signaling has a central role in cell proliferation & differentiation
What regulates retinoic
acid levels
Cell can regulate retinoic acid by feedback so if the cell is exposed to high levels of the retinoic acid 2 things can happen to maintain tight control:
1. LRAT expression gets upregulated so retinol is stored as retinyl ester instead of being converted to the acid
2. CYP26a1 breaks retinoic acid down to polar metabolites
causes of vitamin A deficiency in developing countries
- malnutrition (developing world) - bland diet
- Fad diets (developed world) - bland diet
- Clinical conditions affecting lipid absorption (developed world) - fat malabsorption, gastric bypass surgery
symptoms of vitamin A deficiency
- 11-cis-retinal: night-blindness (nyctalopia)
- All-trans-retinoic acid: ocular defects, Impaired immunity, Impaired growth, Birth defects
ocular lesions
damage to cornea linked to retinoic acid’s role in maintaining epithelial integrity
* xeropthalmia: Severe vitamin A deficiency will manifest as keratinization (hardening/scarring) of the cornea
Stages of xeropthalmia (WHO)
- Night blindness (XN) > reversible
- Conjunctival xerosis (X1A) > reversible
- Bitot’s spots (X1B) > reversible
- Corneal xerosis (X2) > can be blinding (Non reversible where cornia essentially melts away)
- Corneal ulcer (X3) > blinding (non-reversible)
What can ocular lesions correlate with?
Severity of ocular lesions also correlates with increased risk of death»_space; effects on immune system
* Increased mortality in vitamin A deficient populations
How is increased mortality in vitamin A deficient populations associated with impaired immunity?
- Decreased barrier function of epithelia (“first line of defense”), increased susceptibility to urinary tract infections and respiratory infections because the mucous membranes dry out become cracked and more susceptible to pathogen entry
- VitA is important for differentiation of immune cells so with deficiency there is impaired immune response thereby increased severity and duration of disease
Most clinically significant diseases with vitamin A deficiency
- Pneumonia
- Malaria
- Measles
- Diarrheal diseases
growth retardation with vitamin A deficiency
corneal disease has more stunted growth than those with bitots spots
congenital birth defects with vitamin A deficiency
Conclusive data in humans is lacking.
* Case reports and animal studies suggest that VAD is associated with malformation of most organ systems
* Limb defects, kidney defects, eye defects
short term prevention of Vitamin A deficiency
supplementation with mega doses of preformed vitamin A and sometimes coupled with immunization programs
* Retinoic acid is active and it gets used or broken down faster so the huge dose of preformed will maybe establish stores and then hope it can sustain body more long term
long term prevention of vitamin A deficiency
- Promotion of vitamin A-rich foods: feasible, but limited by regional availability, seasonality, expense
- Fortification of staple foods such enrichment with beta-carotene seen in golden rice and orange maze but this is genetically engineered and is controversial
Categories of vitamin A toxicity
- Acute toxicity
- Chronic toxicity
- Teratogenicity
acute toxicity of vitamin A
Consumption of a single high dose of vitamin A (>200,000 IU)
* Leads to increased intracranial pressure, causing headache, nausea and vomiting, blurred vision, altered state of consciousness, loss of motor coordination, skin lesions, and possibly death
* liver of polar bears
chronic toxicity of vitamin A
Long-term consumption of high amounts of vitamin A (25,000 IU/day) typically associated with dietary supplements, increasing incidence
* Headache, fatigue, goruchiness, Intracranial hypertension, skin lesions, hair loss, bone pain, liver damage, irritability
Teratogenicity of vitamin A
Excess vitamin A consumption during pregnancy (>10,000 IU/day)
* Results from supplement use (>10,000 IU/day) or prescription drugs (i.e. accutane/13-cis-retinoic acid for acne)
* Increased rate of miscarriage, multiple abnormalities possible
Simple therapeutic applications of vitamin A deficiency/ toxicity
- Symptoms of vitamin A deficiency corrected with supplementation
- Symptoms of vitamin A excess corrected by withdrawing vitamin A excess from the diet
vitamin A in cosmetic
- increased collagen expression
- changes in skin epithelium‘
- firmer skin
vitamin A role in acne
IN Acne vulgaris retinoic acid may inhibit epithelial cell proliferation drying up the cells that produce the wax and oil causing the acne
vitamin A role in cancer
treatemment in pediatric acute promyelocytic leukemia whereby retinoic acid causes cancer cell differentiation and therefore less proliferative
* Untreated 1 month survival rate but with treatment greater than 10 year survival
vitamin A role in male contraception
Retinoic acid is required for spermatogenesis so inhibitng vitamin A signalling would stop this
* problem of off target effects though and blocking signalling in other important body functions that require vitamin A
