Skildum: Vitamins Flashcards
Which cofactor is not required by the pyruvate dehydrogenase complex?
Biotin (carboxylation cofactor)
What are the fat soluble vitamins?
A, D, E, K
What is the biologically active form of vitamin A?
all trans retiniol
What are the structural elements of Vit A?
B-Ionine ring
branched polyunsaturated chain
alcohol
What can the alcohol of trans-retinol be converted to in the body?
aldehyde
carboxylic acid
ester w/ FA (palmitate)
What are the dietary forms of Vit A?
retinyl-acyl esters
carotenes (two molecules of retinol)
BOTH can be converted to all trans retinol
What is vit A found in?
Red, yellow, orange fruits and vegetables
*carrotts
What are lycopene, lutein, canthaxanthin?
Other forms of Vit A
What are the circulating forms of vit A?
carboxylic acid
retinoic acid
these are exported into the blood
What happens to the esterified retinoic acid esters?
Transfered into chylomicrons> enter the lymph system
What happens to retinoic acid that enters the blood?
Majority enters the liver (first organ that gets a crack at vits and nutrients)
What stores Vit A?
Vit A>
taken up by hepatocytes>
esterified to fat>
stored in stellate cells (enlarged stellate cells> vit A toxicity)
What mediates retiniol homeostasis in the body?
hepatocytes
What are the sources of retinyl to the hepatocytes?
dietary: chylomicrons
stored: stellate cells
Retinyl esters g out to…
Stellate cells (storage) VLDL (to tissues)
Retinol goes out to the serum in complex w/..
transthyretin
RBP
Retinoic acid goes out to the serum complexed to..
albumin
What are the functions of Vit A in the body?
Vision
Vit A def?
night blindness
Vit A toxicity?
blurred vision
How does light signaling through the eye reach neurons in the brain?
Rhodopsin (Opsin-cis-retinal)> Light> conversion to trans-retinal> activates heterotrimeric G protein> closure of Na channel> hyperpolarization of rod cell> signaling to neuron
Retinoic acid acts as a ligand for RAR, RXR and PPAR which act as…
activated TFs
What does retinoic acid as a transcription activator stimulate?
- differentiation of goblet cells (gut)–> affect absorption
- apoptosis of cancer cells (anti-cancer properities)
- maturation of dendritic cells
- recruitment of Ab secreting cells to small intestine
What does retinoic acid TFs inhibit?
keratinization
Carotenes can be cut by monooxygenase to form…
molecules of retinal
W/out being cut, carotenes act as ….
antioxidants b/c their double bonds can neutralize singlet oxygen and free radicals
What are the clinical sxs of Vit A def?
anorexia retarded growth increased susceptibility to infections alopecia keratinization of epithelial cells
eyes: NIGHT BLINDNESS, xeropthalmia, bitot’s spots
How do you diagnose Vit A def?
look at the relative dose response:
Measure plasma retinol conc>
give oral bolus of retinyl>
measure plasma retinol conc after 5 hrs
The HIGHER the RDR (liver and stellate cells aren’t maintaining homeostasis) the more the body is relying on short term dietary vit K, rather than liver and adipose stores.
RDRs> 20% indicate the liver is NOT maintaining serum vit K
What is the tolerable upper limit for Vit A? And what SE are associated w/ large doses?
3000 RAE/day
nausea, vomiting, blurred vision, HA, desquamation of skin, alopecia, ataxia, liver damage, conjunctivitis, eye pain
What vitamin and common acne medicine is a teratogen in high doses?
Vit A
Acutane
What are the two types of Vit E?
- tocopherols (saturate 16 C acyl chains)
2. Tocotrienols (polyunsaturated 16 C acyl chains)
Where is Vit E found?
plant oils (PALM OIL, sunflower oil, canola oil, wheat germ)
Describe Vit E digestion/absorption (parallels fat digestion and absorption!)
Tocopherols, tocotreinol-acyl esters> pancreatic lipase> tocopherols, tocotrienols> intestinal epithelial cell> chylomicrons> tissues> chylomicron remnants> liver> VLDL> tissues
What type of vit E sterioisomers are exported in VLDL?
RRR
Where does vit E function?
Lipid bilayers in intracellular and plasma membranes.
The phenolic hydroxyl can distribute and stabilize singlet oxygen and free radicals as part of cellular oxidative stress defense
What can regenerate Vit E when oxidized?
ascorbate (vit C)
What does vit E inhibit?
Vit K absorption and metabolism
What people have Vit E def?
Absorption problems: premature infants chrons short bowel syndrome inherites lipoprotein disorders
A pt presents w/ myopathy, hemolytic anemia, peripheral neuropathy, ataxia, and loss of vibratory sense. Dx?
vit E def
What is the TUL of Vit E?
1000 mg/day
not very toxic
What is the main form of Vit K in the diet?
phylloquinone from leafy green vegatbles
What produces menaquinones?
fermentation (in gut, cheese)
Have variable numbers of isoprenoid subunits on the acyl chain
What is a synthetic vit K used in animal feed?
menadione
Describe vit K digestion/absorption.
phylloquinone, menaquinone> intestinal epithelial cell> chylomicrons> tissues> chylomicron remnants> liver> VLDL> tissues
Where is Vit K stored?
cell membranes, especially the lung, kidney, bone marrow, adrenal glands
What does Vit K do in target cells?
Acts as a cofactor for glutamyl carboxylase
What does glutamyl carboxylase do?
coarboxylates gluatmic side chains on blood clotting proteins
What inhibits vit K epoxide reductase?
coumadin
What cofactors are dependent on Vit K dependent carboxylation?
Factor IX (Christmas factor), Factor VIIa, Factor X (Stuart factor), and prothrombin
Vit K def can affect what populations?
Infants (milk is low in vit K)
People w/ absorption disorders
A severe Vit K def can manifest as what type of disorder?
coagulation disorder–> increased PTT and increased bleeding
Is there a TUL for vit K?
no but Menadione causes liver toxicity at high doses
Where is vit D found?
animal origin: liver, eggs, fatty fish
shitake mushrooms
fortified dairy products
Vitamin D can be synthesized de nove from ….
cholesterol
What is required to make active vit D3?
metabolism of skin, liver, kidney
What is the most important fxn of Vit D?
Ca homeostasis
How is Ca homeostasis maintained in the kidney?
When the serum Ca is below a set point> parathyroid> PTH> kidney> 1 alpha hydroxylase> 1,25-OH D2> bone and gut
What does low serum Ca conc trigger in the bone and gut?
bone- mobilization of bone Ca
gut- increased Ca uptake
What is the dietary form of Vit D and how is it abosrbed?
cholecalciferol
passive diffusion w/ fat into intestinal epithelial cells>
transported to tissue in chylomicrons>
taken up by liver in chylomicron remnants
What is the main form of Vit D circulating in the blood and the form measured to assess vit D status?
25-hydroxycholecalciferol
What is considered a healthy amt of vit D?
30-40 ng/mL
Where makes the biologically active 1,25-OHD3?
Acyl hydroxylation in the kidney in response to PTH (produced in response to low Ca)
What is VDR?
ligand activated TF
What genes are regulated by vit D (VDRE)?
calcium transport proteins: calbindin, TRPV6, PMCA1b
Activated VDR increases expression of…
- Ca channel TRPV6 at the brush border
- Calbindin in the cytoplasm (chaperones Ca from luminal to basolateral side)
- Ca ATPase pumps at the basolateral membrane
How does VDR affect tight junction permeability to Ca?
Low Ca conc–> high vit D conc–> claudin is disrupted–> tight junctions are not so tight–> paracellular transport of Ca and other substances
Rickets is associated w/ what def? What is rickets?
Vit D
seizures, growth retardation, failure of bone mineralization (osteomalacia)
What can cause vit D def?
dietary
genetic
secondary to absorption problem like Chrons
What vitamin is most likely to have toxic effects?
Vit D
What is hte TUL of vit D?
4000 IU for age 9+
What are the toxic affects of Vit D?
When serum 25-OHD3> 500 ng/mL calcification of soft tissues (kidneys, heart, lungs, blood vessels), hyperphosphatemia, HTN
(too much Ca uptake from the gut–> Ca going to where you don’t want it to be)
s
Stem cells secrete Wnt–> maintains stem cells in a dedifferentiated state
B-cat is in association w/ actin cytoskeleton or free in cytoplasm. In an unstimulated cell it binds with the APC protein–> phosphorylation–> ubiquitination and degradation of beta catenin. Normally Beta cateninin is sequestered on teh cytoskeleton or ubiquinated and deegraded.
Wnt binds frizzle and it blocks the GSK3B that phosphorylates B catenein and signals disuprtion through the proteasome. Wnt stabalizes b catenin some enters the nuculeus and becomes a TF.
What happens in the absence of Wnt?
B catenin is phosphorylated by the APC/axin/GSK3/CK1 complex.
Phosphorylation of b-catenin results in ubiquination and degradation in the proteasome.
What happens when Wnt is present?
Wnt binds frizzled receptor>
inactivation of the APC/axin/GSK3/CK1 complex>
B catenin remains unphosphorylated>
unphosphorylated b catenin accumulates>
translocates to the nucleus>
binds Lef1/TCF>
activates trxn of target genes (cyclin D1 and myc)
What promotes differentiation of intestinal epithelial cells?
Gradient of APC and Beta catenin
crypt–de differentiated and have more replication potential (beta catenin)
villus- terminally differentiated, more APC present
What occurs early in the development of colorectal cancer?
loss of fxn mutations in APC
APCmin mice develop…
multiple spontaneous tumors
VDR null mice recapitulate the phenotype of…
rickets (vit d def)
VDR null mice have elevated…
cylcin D expression
VDR null mice have decreased expression of…
p21 and p27 expression
DHFR is an E2F regulated gene. What level of DHFR expression would you predict in tumor cells from VDR knockout mice relative to tumor cells from wild type mice?
DHFR expression is HIGHER in tumors from VDR knockout animals
Tumors WANT to express DHFR
In mice w/out vit D receptor, their tumors have more D1 (oncogene driving cell growth)–> RB–> E2F–> TF for DHFR and many other things.
Vit D receptor is beneficial in keeping colorectal cells in a less dividing phenotype.
How does high conc of Vit D relate to the incidence of colorectal adenoma?
High conc of Vit D REDUCES the incidence of colorectal adenoma
