401 Exam 3

• Retinol (alcohol)
• Retinal (aldehyde)
• Retinoic Acid (RA)

• Carotenoids that can be converted to retinol
• -Beta- carotene, beta-cryptoxanthin, lycopene, canthaxanthin, lutein

• Free retinol
• -not present in food
• -present as precursor fatty acid esters (i.e. retinyl palmitate)
• *animal products including egg yolks, butter, whole
• milk, liver and fish liver oils
• Carotenoids
• -red, orange and yellow pigments made by plants
• -beta carotene is pigment w/ greatest Vit A activity

-12micrograms beta carotene or 24 microg other carotenoids= 1 RAE

• -often complexed to PTN (release requires pepsin in stomach and proteases in SI)
• -release from fatty acids (esterase abd lipases)
• -released carotenoids and retinols in SI are incorporated into micelles

• 70-90% of retinol absorbed
• 20-50% of carotenoids absorbed

• -Beta carotene can be converted to retinal and then be reduced to retinol or oxidized to RA
• -Retinol is acetylated (reesterified to RE)

• -Primary pathway involves cellular retinol-binding protein (CRBP) II
• -CRBP II binds both retinal and retinol
• -Non-specific ptn may also bind retinol when in high amounts
• *re-ester requires acyl CoA retinol acyl transferase
• (ARAT)

• binds both retinal and retinol
• -directs the reduction of retinal to retinol
• -directs the esterification of retinol to retinyl esters
• *lecithin retinol acyl transferase (LRAT) transfers acyl
• group to form retinyl palmitate

• CMs
• -removal of RE, retinol and carotenoids on route to liver by extrahepatic tissues
• *bone marrow, blood cells, spleen, adipose, muscle,
• lungs, kidneys
• CM remnants removed by liver

• Retinyl Esters
• -hydrolyzed to free retinol
• -retinol binds with CRBP
• -enzymatic metabolism

• Retinol not metabolized or transported out
• -stored as RE primarily in stellate cells

• -esterification by LRAT or ARAT
• -oxidation of retinol to retinal
• -phosphorylation of retinol to retinyl phosphate

• -dependent upon synthesis and secretion of retinol binding ptns (RBP)
• -RBP binds retinol (from stellate cells) (holo RBP)
• -complex secreted in plasma

• -holo-RBP interacts with transthyretin (TTR)
• -RBP-TTR complex circulates in plasma
• -Retinol can be taken up from complex

• -retinol removed leaving behind RBP-TTR
• -RBP-TTR then dissociate
• *apo-RBP catabolized by kidney

• by individual cells
• -in cytoplasm, RA binds to cellular retinoic acid-binding ptns (CRABPs)
• *prevent catabolism and direct usage

• Visual cycle (retinal)
• Cell differentiation (retinoic acid)
• ROH essential for reproductive process
• Immune system (for T-lymph funct, antibody response)
• Bone developement
• Antioxidants (Beta carotene)
• Embryonic developement
• Maintenance of normal structure and function of epithelial cells
• Growth

-Vit A deficiency results in excessive deposition of bone by osteoblasts and reduced number of osteclasts

-possess ability to react with and inactivate free-redical reactions in membrane systems and possibly in solution (plasma/cytoplasm)

-prevent oxidation of LDL-C

functs as a hormone to affect gene expression

RA or 9-cis RA taken into nucleus bound to CRABP

• -RA or 9-cis RA binds to RAR (RA receptors)
• -9-cis RA binds to RXR (retinoid receptors)
• -RAR-RXR dimerization permits interaction with specific nucleotide sequences of DNA (genes)
• *regulates transcription to RNA and translation to protein

may signal morphogenesis-evolution and developement

• epithelial cells found in lungs, trachea, skin, cornea, and GI tract
• *directs the differentiation of keratinocytes into mature
• epidermal cells
• *also directs keratin synthesis
• *directs differentiation of epithelial keratinizaing cells
• in mucus-secreting cells in vitro

Vit A deficiency results in poor growth

• admin of ROH or RA can stimulae impaired growth
• *particularly growth of epithelal cells
• *stimulate the # of specific receptors for GF

• Vit E
• -is needed for cleavage of beta carotene into retinal
• -may protect substrate and product from oxidation

May prohibit both Vitamin E and K absorption

transport and use of the vitamin depends on several vitamin A binding proteins

• Zinc deficiency interferes with Vitamin A metabolism
• -decreased food intake
• -reduction in synthesis of RBP
• -decreased mobilization of ROH from its storage as RE
• -alcohol dehydrogenase requires Zn

Vitamin A def. may result in microcytic anemia

Vit A may affect iron metabolism or storage or differentiation of RBC

• -oxidize RA to a variety of matabolites
• *excreted via bile into feces (70% of vit A metabolites)
• * urinary excretion accounts for remaining 30%

• -900 micrograms for males
• -700 for women

-UL=3000 micrograms/d (preformed vit only)

• -common in developing companies
• *inadequate intake is common in children <5yo

• -increased mortality
• *anorexia, retarded growth, increased susceptibility to infections, keratinization of epithelial cells of skin with failure of normal differentiation

• Night blindness
• Xerophthalmia
• Corneal ulceration/keratomalacia

• -Those with increased needs
• *fat malabsorption, intestinal parasites, protein def.,
• chronic nephritis
• -Measles
• *depresses Vit A status
• *WHO and UNICEF recommend supplements for children with measles or living in countries where measles in prevalent

impaired production of rhodopsin in rods (reversible)

• Reversible
• -abnormal dryness and thickening of conjunctiva and cornea of eyes.
• *conjunctival change include disappearane of goblet cells, enlargement and keratinaization of epithelial cells
• *Bitot's spots-white accumulations of sloughed cells; accumulate over the keritinized epithelial cells

softening and necrosis of cornea

-irreversible

• In adults
• -dry, itchy skin, bone and muscle pain, conjunctivitis, cirrhosis

• -100,000 IU/d for short period=toxic
• -25,000-50,000 IU/d= toxic
• -10,000 IU/d avoids toxicity in most
• Bet carotene is non toxic

Bitot's spots

Measurment of dark adaptation threshold

Electroretinograms to measure the level of rhodospin and its rate of regeneration

• Plasma ROH concentration
• -more accurate if tissue stores exhausted
• Measurement of changes in plasma ROH concentration before and 5 hours after oral admin of RE in oils
• -process referred to as Relative Dose Response

• Vitamin D3 (cholecalciferol, D2
• Active form is 1,25- (OH)2 D3 (calcitriol)

• Cholesterol ->
• 7-dehydrocholesterol ->
• Previtamin D3 ->
• Vitamin D3 (cholecaciferol) ->
• 25-OH Vitamin D3 ->
• 1,25 (OH) 2 Vitamin D3 (calcitriol)

• Sunlight
• Animal
• -eggs, butter, liver, fatty fish
• -fortified products like milk and margarine
• Plants, ergosterol can be activated by irradiation to from ergocalciferol (Vit D2 or ercalciol)

-7-dehydrocholesterol is made in sebaceous glands of skin and secreted onto the surface and then reabsorbed into various layers of skin

• -exposure to sunlight
• *converts some of 7-dehydrocholesterol to previtamin D3

bile salts, micelle, incorporation into CMs

~50% is absorbed

• -CMs transport ~40%
• *some holecalciferol may be transferred from CM to DBP and delivered to extrahepatic tissues
• -~60% of cholecalciferol is transported by DBP
• *skin+ diet (DBP=Vit D binding protein)
• -Both go to liver
• *extrahepatic tissues remove Vit D3 en route

• -Hydroxylated at carbon 25 to form 25-OH D3
• -Most gets secreted in blood and taken to kidney by DBP

Second hydroxylation occurs at 1 position forming 1,25- (OH)2-d3 (calcitriol)

Active form of Vitamin

• -1-hydroxylase is regulated by many factors
• *PTH and low blood Ca++ stimulate
• *high dietary P intake decreases
• *sufficient amounts of calcitriol inhibit activity
• 1.)24 hydroxylase is stimulated
• 2.)may be involved in bone mineralization or
• represent a step in degradation process

read in book!

works with PTH in increasing calcium and phosphorus reabsorption

• Works with PTH in directing mobilization of Ca++ and P from bone to mnormalized blood Ca++ levels
• -may be mediated by calcitriol-induced cell differentiation of hemopoietic cells to osteclasts
• -or may be mediated by calcitriol-induced increases of osteoclast activity

mediate bone resorption

-hormone produced by thyroid gland

-released when blood calium levels rise above normal

-promotes mineralization of calcium and phosphorus in bones

• Elevated serum calcitriol and elevated serum Ca++ cause decrease in PTH through feedback loops
• -elevated serum calcium inhibits PTH secretion
• -calcitriol decreases transciption of the gene for preparathyroid hormone
• *interacts with Vit D receptors

• Protein found in bone matrix and dentine
• -secreted by osteblasts
• -associated with new bone formation

*Calcitriol may be important, along with Vit K, in the synthesis of osteocalcin

• Cell differentiation
• -triggers differentiation of stem cells to osteoclasts
• *may also induce release of osteoblast-derived resorption factors that stimulate osteclast activity

cancer cell proliferation and growth and stimulates epidermal cell differentiation, while preventing proliferation

• -lack of differentiation (specialization)
• -rapid growth or proliferation

• Vitamin D receptors (VDR)
• -breats, lung, skin, colon, bone

1,25 (OH) 2D induces cell differentiation and/or inhibit proliferation of a number of cancerous and noncancerous cell types maintained in cell culture

• Geographic distribution of colon and breast can. is similar to gegraphic distribution of rickets.
• -decreased sunlight exposure and diminished vitamin D nutritional status may be related to an increased risk

• Insulin dependent diabetes mellitus
• -beta cells of the pancreas
• Multiple sclerosis
• -myelin producing cells of CNS
• Pheumatoid arthritis
• -collagen producing cells of the joints

Ca, P, Vit K

• -converted to 1,24,25- (OH)3D3 and then further catabolized and excreted in bile
• -feces major route of excretion
• -<5% of metabolites are excreted in urine

• -in 2010 the Food and Nutrition Board of the institute of Medicine set a Recommended Dietary Allowance based on the amount of Vit D needed for bone health
• -based on age
• -adults 19-50=15 mcg
• -UL adults 19 y and older = 100 mcg

Rickets in infants and children

Osteomalacia (soft bone) in adults

• failure of bone to mineralize
• -long bones of legs bow
• -knees knock as weight-bearing activities begin (walking)
• -spine becomes curved and pelvic and thoracic deformities

• -impaired Ca absorption
• -mineralization of bone is impaired
• -bone matrix becoes demineralization- bone pain and softening

Obesity

• -fat malabsorption
• -disorders affecting parathyroid gland, liver and/or kidney
• -infants on breast milk
• -aging may reduce synthesis of cholecalciferol
• -lack of sunlight (location, dark skin, burka)
• -diet, vegan, lacto-veg.

• NOT due to excessive exposure to sunlight
• -doses of 10,000 IU/d may result in hypercalcemia
• *calcification of soft tissues (kidney, heart, lungs, blood vessels)
• *HTN, anorexia, nausea, renal failure, death

Ca2+, divalent cation

Calcium Phosphate Hydroxyapatite

3 or more servings milk/dairy foods

calcum-fortified foods

Calcium/vitamin D supplements

• 5 or more servings vegetables and fruit
• -potassium, magnesium, zinc, copper
• -vitamin K and vitamin C

• DRI/RDA
• 19-50 yo= 1,000 mg Ca
• 51-70= male 1000, females 1200
• >70= 1200 mg

UL-2,500 mg

• milk, yougurt, buttermilk, cheese
• Canned salmon with bones
• calcium fortified foods
• -OJ, soy drinks
• -breakfast cereals, cereal bars
• tofu made w/ Ca sulfate

• -Lactose intolerant or allergic to milk
• -avoid milk/dairy
• -on strict wt loss diet
• -over 50 yo
• -not enough sun exposure
• -long term steroid therapy

• -Absorbed via active (vit D, PTH)
• -also passive, paracellular, nonsaturable
• -in upper part of sm. intestine (ileum)
• -large intestine, bacteria release Ca from fermentable fibers (pectin)

• about 30% for adults
• about 75% for children

• acidity of GI tract
• Lactose, other sugars, protein
• vitamin D

• nonfermentable fibers, decrease transit time
• fermentable fibers, binds
• phylates (legumes, nuts, cereals) binds
• oxalates (veg, fruits, nuts, tea) chelates
• unabsorbed fat (steatorrhea)
• excess P or Mg 2+, menopause, age

• Vit D
• sugars and sugar alcohols
• protein

• fiber
• phytate
• oxalate
• excessive divalent cations
• unabsorbed fatty acids

• iron
• fatty acids

• -ionized form (60%)
• -protein-bound (aprox 40% albumin)

• Feces- unabsorbed and endogenous Ca
• Urine
• Sweat (small amounts)

• 1. bones formation and maintenance
• -cortical bones:dinse, compact
• -trabecular bone: spongy, inner matrix
• -bone strength: bone mineral density test

-remove old, build new, 15-30% of the bone is rebuilt each year

• bone cells that secrete a collagen matrix that forms the support structure of bone
• they then secrete bone mineral, which strengthens the bone

bone cells that constantly break down the bone network

• -Metabolic roles
• -formation of dentin
• -blood clotting
• -muscle contraction
• -phosphorylase kinase activate phosphatase
• -nerve conduction
• -regulation of intracellular membrane transport

• -osteoporosis
• -rickets/osteomalacia

• -impaired dentition
• -impaired skeletal developement
• -elevated blood pressure??

• Calcium is deposited
• -during childhood, teen and young adult years
• -when consume enough Ca and Vit D
• Calcium is withdrawn
• -during older adult years
• -when do not consume enough Ca and Vit D

• Porous bones
• -bones have lost Ca and other minerals
• -bones are fragile
• -bones fracture easily

• Female
• Increasing age
• Thin, small bones-BMI<19
• Caucasian or asian
• Fam Hx
• High sodium
• High protein intake
• Abnormal menstrual hx
• Have has an eating disorder or times of strict dieting
• Medical conditions
• Medication use

• bone fraccture after 40
• rheumatoid arthritie
• thyroid disorder
• parathyroid disorder
• poorly controlled T1DM
• lactose intolerance
• digestion disorders

• inactive lifestyle
• dt low in Ca
• little sun exposure and diet low in Vit D
• few fruits and vegetables
• drink excess alcohol
• current or former smoker
• lots of caffeine
• high sodium and protein

• -disruption of normal parathyroid function may result in increase blood Ca++
• -hypercalcemia is a condition called Ca rigor
• -excess Ca++ may interfere with absorption of Zn
• Increased risk of urinary stone formation in susceptible indivs