NUTR 620 Vitamin A
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A substance that provides nourishment essential for growth and maintenance of life: proteins, vitamins, minerals, etc.
What are some modulators of vitamin action? 7
Bioavailability, bioconversion, matrix (type of storage in food - crystal vs. lipid), effectors of absorption (diet), nutrition status of host , genetics (polymorphisms in enzymes), host factors (illnesses)
What are sources of vitamins? 3 What are some demands of vitamins? 6
Sources: quality, quantity, bioavailability
Demands: Poor diet, diarrhea, pregnancy, lactation, premature, illness/fever
What are 5 characteristics of vitamins?
What are 3 exceptions of vitamins that can be synthesized by humans?
- 1. Organic
- 2. Essential (cannot be synthesized by humans)
- 3. Found in small amounts in food
- 4. Function is NOT structural or energy-producing
- 5. A deficiency syndrome will arise by its absence/underutilization
Vitamin D (sun), choline and niacin (depending on adequate resources)
1. What is the vitamin caveat? (2)
2. How many recognized vitamins/groups of vitamins are there?
3. Define vitamers
4. Define provitamins (ex?)
1. Some compounds are vitamins for one species, but not for each other. Also, some are vitamins only under certain dietary or environmental conditions.
3. Vitamers - family of vitamins that function similarly.
4. Provitamin - precursor to active vitamin.
Carotenoids can be metabolized to vitamin A
What are the two classes of vitamins? How are vitamins categorized?
What are the fat-soluble vitamins? What is similar about them?
What are the water-soluble vitamins? Are they similar?
Fat-soluble vs. water-soluble; based on solubilities.
ADEK - structurally similar.
B vitamins, vitamin C - yes, but not structurally.
1. What is a mineral? (name 5 characteristics)
2. What are common causes of mineral deficiencies? (4)
1. Inorganic, essential, needs satisfied by small (mg) or trace (ug) amounts, found in food in small amounts, obtained from food and water/air.
2. Inadequate intake, impaired absorption, increased demand, increased urinary loss
1. Are minerals changed during digestion?
2. How are minerals affected by heat, light, or alkalinity?
3. What are two functions of minerals?
- 1. No
- 2. Not at all
- 3. Needed for some enzyme activity and can play a structural role.
How do vitamins differ from minerals?
What are the types of dietary reference intakes (DRI) for micronutrients? What are the differences?
Which is for groups? Which is for individuals?
1. Recommended dietary allowance (RDA) - average daily intake sufficient to meet most people's requirement.
2. Adequate intake (AI) - only if RDA can't be established - based on observed nutrient intakes in healthy people
3. Tolerable Upper Level Intake Level (UL) - highest daily intake unlikely to pose risk of toxicity.
4. Estimated Average Requirement (EAR) - amt estimated to meet requirement of half of all healthy individuals in a population.
EAR - groups; all else (RDA, AI, UL) are for individuals.
Where do EAR, RDA and ULs compare to harm from deficiency vs. harm from excess?
What are problems with DRIs? (2)
- 1. Suffered from lack of transparency and consistency.
- 2. Diff in ref values derived by various groups despite same database
1. What units make up fat-soluble vitamins?
2. What is the name of the vitamer for vitamin A?
3.What are the 3 types of carotenoids?
- 1. 5-C Isoprenoid units
- 2. Retinoid family
- 3. alpha, beta, gamma carotene
What does a retinoid look like?
What is 1 retinol equivalent (RE) in terms of all-trans retinol? all-trans b carotene in dietary supplements? all trans B carotene in foods? Other provitamin A carotenoids in foods?
- 1. 1 ug all-trans retinol
- 2. 2 ug all-trans B-carotene in dietary supplements
- 3. 12 ug all-trans B-carotene in foods
- 4. 24 ug other provitamin A carotenoids in foods.
What are sources of vitamin A? (4 main groups -name examples in each)
- 1. Breast milk (transfers retinol from mother to infant). Depends on stage of lactation
- 2. Retinoids - meat, liver, egg yolks dairy
- 3. Carotenoids - yellow/red fruits or veggies and dark leafy greens
- 4. Fortified foods (margarine)
1. What does B-carotene convert into? Via what enzyme? What cofactor is needed? Where is this enzyme found? (2)
2. What can retinal convert into? Which is reversible? What enzymes? What cofactor and reducing agents?
3. Which is reversible?
4. What can retinol convert into? With what enzyme? What cofactor?What type of rxn is this? What else is required?
5. Which rxn is tightly regulated? Which one serves as a ligand for RXR and RAR?
1. TWO retinals via B-carotene monoxygenase 1 (BCOM1) with Fe. It's found in the intestinal mucosa and liver.
2. Retinal --> Retinol via retinaldehyde reductase with NADH. Retinal --> retinoic acid via retinal oxidase (irreversible.
3. Retinal <--> Retinol.
4. Reverse rxn is retinol --> retinal via alcohol (retinol) dehydrogenase with Zn as cofactor via oxidation with NADH/NADPH.
5. Retinal --> Retinoic acid. Retinoic acid serves as a ligand for RXR and RAR.
What are the four main types of rxns that vitamin A can undergo? and what are the purposes?
- 1. Redox
- 2. Esterification (storage as retinyl ester - lipid)
- 3. Conjugation (bile excretion)
- 4. Isomerization (interconversion of all-trans forms of vitamin A and cis forms - most important in eye)
Describe absorption of vitamin A in intestinal mucosa into lymph/blood.
- 1. Retinyl esters are hydrolyzed into retinol and retinol and b-carotene are packed into micelles.
- 2. Micelles diffuse across brush border from intestinal lumen into enterocytes.
- 3. B-carotene --> retinal --> retinol and retinol can undergo two pathways:
- (1) Low-affinity route: UNCOMPLEXED retinoil is catalyzed by ARAT (acylCoAacyltransferase) into retinyl esters and put in chylomicrons.
- (2) High-affinity route: Retinol is first complexed with CRBPII (cellular retinol binding protein), then is converted into REs thanks to LRAT (lecithin retinol acyltransferase)
- 4. Chylomicrons are released into the lymph/blood.
What does ARAT do? What does LRAT do? What do they stand for? Which enzyme is regulated by vitamin A and how?
What is most abundant RE?
- 1. ARAT: converts uncomplexed retinol into retinyl esters
- 2. LRAT: converts complexed retinol-CRBPII into restinyl esters.
3. LRAT - Vitamin A regulates gene expression of LRAT - retinoic acid increases LRAT expression, while vitamin A depletion decreases LRAT expression (positive feedback! makes sense bc its high affinity - high volume).
What happens to REs once they're released into blood from gut?
- 1. REs in chylomicrons are absorbed in liver, REs are converted to retinol via RE hydrolases
- 2. Retinol can then (1) Be released into blood and bind to RBP (retinol binding protein) for transport in plasma to target tissues or (2) Go to stellate cells in liver and convert to retinyl esters for storage via LRAT.
How is retinol uptaken in target tissues? (2)
Which is more dominant?
1. Via specific receptor-mediated mechanisms (STRA-6 - dominant mechanism) or by nonspecific partitioning (moving) of retinol into plasma membrane due to hydrophobic nature of retinol
Where is most vitamin A stored?
Is plasma content of RBP strictly maintained?
Where is the only site of catabolism of RBP?
What is the purpose of TTR?
How is retinoic acid carried around?
In the kidney.
TTR stabilizes complex, increases binding affinity of RBP to retinol and decreases glomerular filtration of retinol
Via albumin (does not use RBP)
What do vitamin A levels regulate?
- 1. BCOM1 levels
- 2. LRAT gene expression
What is the purpose of LRAT and where is it used?
What happens to retinol once it enters cell of target tissue? 6 options...
Mechanism essentially has 7 steps
1. Combines with CRBP. If RA, can bind to retinoic binding proteins (CRABP I and II
) or retinaldehyde binding protein (CRALBP) or can combine with nuclear retinoic acid receptors (RAR and RXR)
- 1. Retinol binds to RBP
- 2. Complex enters cell via STRA6
- 3. Retinol is oxidized to retinal via RETINOL DH
- 4. Retinal --> all-trans RA via retinaldehyde DH
- 6. All-trans RA binds to CRABP I and II and enters nucleus for gene regulation or cytoplasm for paracrine signaling
- 7. Retinoic acid is regulated by CYP26 class of P450 enzymes.
- (1) Retinol (CRBPI) --> Retinoic Acid
- 2. Binds to CRABP I/II and enters nucleus or goes to cytoplasm for paracrine signaling
Where does adipose tissue take up retinyl esters from? What type of transport does adipose tissue NOT use? Why?
What is required for release from adipocytes? (2)
- 1. Chylomicrons
- 2. Doesn't use STRA6 or nonspecific partitioning bc it gets it from chylomicrons, not RBP
- 3. Requires lipase and conversion of adipocyte retinyl esters to retinal
1. What happens to plasma retinol when you eat a lot of vitamin A vs. not a lot?
2. What is retinol homeostasis regulated by? (2)
3. What happens when you have renal dysfunction
- 1. Not much - retinol levels in plasma are confined in narrow range.
- 2. (1) regulation of CRBPII expression in enterocytes (2) Regulation of enzymes that esterify retinol and hydrolyze retinyl esters (LRAT, ARAT, and REH)
- 3. Increases in plasma retinol levels
What are important functions of Vitamin A? (6)
- 1. Vision
- 2. Epithelial differentiation - accutane, leukemia
- 3. Immune function (thymus/lymphoid organs)
- 4. Reproduction - spermatogenesis
- 5. Reproduction - embryonal development
- 6. Epigenetics
What does the process of vision rely on?
What specifically happens in rod cell?
1. Light-induced isomerization of chromophore from 11-cis retinal
to all-trans retinal
resulting in change of conformation and activation of photoreceptor in rods.
2. 11-cis-retinal combines with opsin to form rhodopsin, light hits, and rhodopsin is disassociated into opsin and all-trans-retinal
all-trans-retinal can exit rod cell to be recycled
How does Vitamin A affect nutrient gene regulation? 4 steps
Which receptor can work with other nuclear receptors? Examples? (2)
- Acts as steroid hormone
- 1. Steroid hormone (All-trans or 9-cis RAR) diffuses into cell
- 2. Binds to receptor (RAR (both) or RXR (only 9-cis) in cytoplasm or in nucleus forming an activated hormone-receptor complex
- 3. Dimerization (homodimerization or heterodimerization) RXR-RXR or RXR-RAR (not RAR-RAR)
- 4. Binding to RXRE or RARE on DNA and work together to affect transcription.
RXR - can also bind to PPAR, vitamin D receptors, etc.
What are the two types of effects from retinoic acid?
- 1. Primary - mRNA creates a protein that directly produces an effect
- 2. Secondary - when Vitamin A creates a protein that acts as a transcription factor to influence mRNA transcription to create another protein
How does vitamin A affect epigenetics?
Retinoic acid activates HAT (histone acetyl transferase) allowing transcription to occur.
Without RA, HDAC is active and removes acetyl group from histones --> no transcription.
How does Vitamin A affect skin? Cancer? (4) Specific examples (2)
- 1. Acne - accutane - teratoge & epithelial differentiation
- 2. Cancer occurs when cells don't terminally differentiate. Retinoids have been used as chemotherapeutic agents bc the promote differentiation, antiproliferation, proapoptoptic and antioxidant effects.
All-trans RA can treat leukemia while 9-cis RA treats Kaposi's sarcoma
What is the leading cause of blindness in children?
What can vitamin A def reliably predict?
1. Vitamin A def
2. Prognosis - 50% of vitamin A deficient children who become blind die within the next 12 months.
What are types of Vitamin A def?
How does Vitamin A def typically progress? (3)
- 1. Primary - inadequate intake
- 2. Secondary - adequate intake, but failures in physiological utilizatino (absorption/transport problems)
Liver RE stores decrease --> plasma retinol-RBP concentrations decrease --> cellular functions of vitamin A are defective
What are symptoms of vitamin A def? Name 5
1. Xeropthlamia (hallmark) - cells change from normal to keratinizing, allowing infection, Bitot's spots and follicular hyperkeratosis (goose bumps)
Loss of appetite, retarded growth, infection, death
What are causes of Vitamin A def? (6)
- 1. Zn deficiency - decreased syn of RBP, etc.
- 2. Recurrent diarrhea (reduces liver reserves)
- 3. Fever - urinary wastage
- 4. Alcohol (oxidant)
- 5. Anything blocking cholesterol/lipid uptake (olestra)
- 6. protein energy malnutrition - inability to make RBP
How does vitamin A affect immune system? 2
RA is important for creating FoxP3+ cells (good T cells) that are ant-inflammatory.
Also helps maintain mucin.
Difference between fortification or enriching?
World's best health investment?
1. Fortification - adding; Enriching - adding more
2. Vitamin A and Zn supplements = world's best health investment $1 investment = $17 in saved healthcare costs
3. To provide vitamin A supplementation at time of immunization (4-6 months)
4. Yellow rice - genetically engineered rice with genes from vitamin A rich marigolds and daffodils in rice.
Is vitamin A toxicity possible? Why would you need high doses?
What increases chances of vitamin A toxicity? (2)
What is a problem with supplements?
What is a problem with RA?
1. Yes, because RA is powerful, but generally catabolized and excreted quickly, so require high doses to see toxicity effects/
2. Alcohol abuse and renal failure
3. Unregulated - Airborne recommends 3x the daily dose of vitamin A
4. Teratogen - leads to fetal malformations
Which 3 carotenoids have no vitamin A activity? (3)
Why are carotenoids good antioxidants?
What form of carotenoids is more bioavailable? Which is less bioavailable? Examples of each?
Is there toxicity or def? What happens if you take too much?
- 1. Zeaxanthin, lutein, adn lycopene
- 2. Multiple conjugated double bonds - good for scavenging free radicals
3. Oil droplets (pumpkin mango) vs. crystals/chloroplasts (dark leafy greens, carrots)
4. No tox or def, but skin can turn orange.
What case studies were associated with vitamin A def? 1
1. Short bowel syndrome --> night blindness. Treatment - IV feeding
How does B-carotene affect lung cancer? Possible answer? take home message?
How does lycopene affect cancer?
What can lutein and zeaxanthin possibly do? (1) by what mechanism? (2)
1. Based on epi studies, B-carotene seemed to help outcomes of lung cancer, but when doing a RCT, found that it led to increase in lung cancer and death (maybe bc retinoids facilitate activation of carcinogens in cigarettes)
Take home message - B-carotene from fruit/veggie-rich diet is protective, but taking pharmacological levels can be dangerous
2. Associated with decreased cancer risks - maybe bc lycopene accumulates in prostate and counteracts mitogenic affects of androgens
3. Help prevent age-related macular degeneration (AMD) by absorbing blue light and acting as antioxidants
What levels is one deficient in Vitamin A? Normal? Toxicity? What happens in each category?
Deficient: 0-500 - decreased cell division, developmental deficiencies - night blindness, xeropthalmia, keratinization, exhaustion, death.
Normal 500-15000 ug REI/day- normal vision, cell development/divisoin
Toxicity over 15000- overstimulated cells, skin rash, hair loss, liver failure, bone fracture, death.
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