LIPID MAPS Lipid Metabolomics Tutorial
Fat Soluble Vitamins
Professor Edward A. Dennis
Department of Chemistry and Biochemistry
Department of Pharmacology, School of Medicine
University of California, San Diego
Copyright/attribution notice: You are free to copy, distribute, adapt and transmit this tutorial or
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Attribution: Edward A. Dennis (2010) “LIPID MAPS Lipid Metabolomics Tutorial” www.lipidmaps.org
E.A. DENNIS 2010 ©
Vitamins: The Family Tree
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Preview: Vitamin A - Retinol
Various “retinoids”
– retinol, retinal & retinoic acid
– retinyl esters
Retinol
• transport in blood
– beta carotene
All-trans retinal
Numerous Functions
– Vision
•
•
•
•
Retinoic acid
11
12
11-cis retinal
(formed by photoisomerization
of all-trans retinal)
all-trans retinal
11-cis-retinal
Growth & Wound healing
especially epithelium
– Reproduction
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Vision- How it works…
• Cis-Retinal acts as a cofactor of the protein opsin to form
rhodopsin.
• It functions in a similar way in rods and cones. But we’ll use rods
as a model.
• Rhodopsin and transducin are embedded in the cell membrane
of the outer rod segment.
• Rhodopsin is the photoreceptor. It is an integral membrane
protein with 7 membrane spanning segments. When a photon
of light hits rhodopsin, it causes the isomerization of cisretinal to trans-retinal. This activates the receptor, causing
it to bind to the heterotrimeric G protein, transducin.
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Retinol from b-Carotene
• Retinal and retinol are readily
interconverted
• Most dietary vitamin A comes
in the form of b-carotene.
– 1 carotene = 2 retinal
– But: inefficient conversion
– Less toxic than retinol
Cleavage
Site
2x
• Safer form of the vitamin
– Found in yellow and dark green
vegetables
• carrots, doc.
b-carotene
Retinal
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Vitamin A Deficiency
• Incidence: Rare in the US
– Seen in people who don’t eat well
• Worldwide, it is the third most common
nutritional deficiency, accounting for
500,000 cases of blindness annually.
• Symptoms
– Loss of acuity & night blindness,
blindness
– Lesions on corneal surface
– Eventually, dermatology problems
• Mechanism: Lack of retinoids
Trivia: Ancient Egyptians
recognized that night blindness
could be treated by eating liver.
– Poor epithelial growth
– Rhodopsin synthesis is impaired
• Treatments: A supplementation
– Better diet
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Vitamin A Toxicity
There are three syndromes of vitamin A toxicity:
• Acute Toxicity (very rare)
– occurs in adults when >200 mg are ingested
– symptoms include nausea, vomiting, vertigo, and blurry
vision.
• Chronic Toxicity (rare)
– occurs with long-term ingestion of doses higher than 10
times the RDA.
– symptoms include problems talking, hair loss,
hyperlipidemia, hepatotoxicity, bone and muscle pain,
and vision problems.
– In postmenopausal women, it has been associated with
increased fracture risk.
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Vitamin A Toxicity
• Teratogenic Effects:
– Synthetic retinoids can be used to treat severe
dermatological conditions including severe psoriasis
and acne vulgaris.
– Synthetic retinoids, like acitretin, cause spontaneous
abortions and severe life-threatening congenital
malformations.
• Women treated with retinoids must not get pregnant at
the time of treatment or become pregnant for up to 3
years after treatment.
• Patients receiving treatment with retinoids must not give
blood for up to three years after treatment.
– The presence of these drugs in plasma can be
demonstrated for up to several years after a person
stops taking them. It could be disastrous if an
unsuspecting pregnant woman received one in a
transfusion, hence the ban.
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Vitamin D - Cholecalciferol
Ergocalciferol
Diet
• Vitamin D is a cholesterol-like
molecule
• Important to bone and calcium
regulation
– Acts more like a steroid
hormone rather than a enzyme
cofactor
• Cholecalciferol (D3) has two sources:
Cholecalciferol
synthesis in skin
– Diet
• plants have ergocalciferol (D2), which
easily becomes D3
• animal flesh has ready-made D3
– Sunlight (UV)
• Converts 7-dehydrocholesterol into
D3 in the skin
7-dehydrocholesterol
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Metabolism of Cholecalciferol (D)
Calcitriol is the active form of the vitamin
– aka: 1,25 (OH)2-cholecalciferol or 1,25-D
Its precursor (provitamin) is cholecalciferol,
native vitamin D
– aka: D or D3
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Vitamin D Toxicity
• Vitamin D can build to toxic levels!
– Most dangerous vitamin!
– Messes up serum Ca++ leading to
hypercalcemia, hypercalciuria and
bone demineralization.
– Intoxication may occur in fad
dieters who consume
"megadoses" of supplements, in
Trivia: In the 1940s and 1950s, a number
patients on vitamin D replacement
of children developed hypercalcemia and
some even had hypercalcemic-induced
therapy for malabsorption, or in
brain injury. This was felt to be a result of
children who overdose on
the high concentrations of vitamin D in
fortified milk products
supplements.
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Vitamin K - Phylloquinone
Vitamin K1
• Made by normal intestinal flora
– Antibiotics can cause a loss of K!
• Two forms exist
– phylloquinone (K1) - plant sources
• spinach, cabbage, cauliflower
– menaquinone (K2) - bacterial sources
• Important in blood clotting
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Vitamin K Function
• Important in Hematology
• Catalyzes g -carboxylation
• Required by liver to make
clotting factors
– Factors II, VII, IX & X
– K = Klotting
– No K = No Klotting
• Inhibited by anticoagulants
like warfarin
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Vitamin K Deficiency
• Incidence: Common in certain groups
– Malnourished people on antibiotics
– Babies whose intestines are still sterile
– Patients on anticoagulants like warfarin
• Symptoms: Spontaneous bleeding
– Hematemesis (bloody vomit)
– Hemarthrosis (blood in joint capsules)
– Spontaneous bruising & bleeding gums
• Mechanism: Lack of vitamin K
– Factors II, VII, IX & X depend on K
• Treatments: K supplements
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Warfarin Overdose
Warfarin
Trivia: Warfarin was
originally developed
as a rodenticide.
• Warfarin has been the standard oral
anticoagulant used in a variety of clinical
settings.
• Patients treated with warfarin frequently
become overly anticoagulated. The most
common causes include drug interaction,
dietary changes and superimposed illnesses.
• If the clotting time is significantly impaired or if
the patient is at a high risk for bleeding Vitamin
K is given to reverse the effects.
• Mechanism of Action: Warfarin is similar in
structure to vitamin K and interrupts the vitamin
K dependent carboxylation cycle by blocking
reduction of the inactive K 2,3 epoxide to the
active form of the vitamin.
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Vitamin E - Tocopherols
Vitamin E
• Several variations exist
– D-a-tocopherol is most potent
• Lipid-media antioxidants
– contrast with vitamin C: a water-media antioxidant
• Found in nuts and meats
• No clear deficiency disease
• Long term effects and safety of
supplementation are unclear.
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Summary of Fat Soluble Vitamins
Vitamin
Active Forms
Function
Sources
Disease
Toxic?
Retinol
ll-cis retinal
many others
Vision, growth
veggies
A deficiency
Somewhat
Cholecalciferol
Calcitriol
Bone and Ca++
regulation
UV light
Dairy
Rickets
Very!
Tocopherols
same
Antioxidant
Nuts, meat
Atherosclerosis?
Not really
Phylloquinones
same
Blood clotting
Colonic flora
K deficiency
Somewhat
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Isoprene Units - A Common Thread
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Example: Recognizing Isoprene Units
2
1
3
Isoprene
(2-methyl-1,3-butadiene)
• Retinol=4 x
Isoprene
• Look for 5-carbon
units
• Double bonds may
be removed or
rearranged
• C2 connects
always to at least 3
other carbons
Retinol
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What About Vitamin Supplements?
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Review of Lipid Metabolism
LIPIDS
CARBOHYDRATES
PROTEINS
fatty acids
glucose
amino acids
Acetyl CoA
malonyl CoA
citrate
fatty acid
neutral lipids
phospholipids
sphingolipids
cholesterol esters
acetoacetyl CoA
HMG-CoA
CO2 + ATP
(energy)
Oversimplified picture
ketone bodies
cholesterol
Organ Localization
BLOOD TRANSPORT
Brain
•
•
•
•
TG on lipoproteins
FA on albumin
Glucose dissolved
Ketone Bodies dissolved
TG
Glucose
(Ketones)
Adipose
FA
Liver
Glucose, FA
(Ketones)
Bile
Muscles
Intestine
Oversimplified picture
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Intracellular Localization
FA
Acetyl CoA
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Acknowledgement
This tutorial is based on an evolving subset of lectures and
accompanying slides presented to medical students in the Cell
Biology and Biochemistry course at the School of Medicine of the
University of California, San Diego.
I wish to thank Dr. Bridget Quinn and Dr. Keith Cross for aid in
developing many of the original slides, Dr. Eoin Fahy for advice in
applying the LIPID MAPS nomenclature and structural drawing
conventions [Fahy et al (2005) J Lipid Res, 46, 839-61; Fahy et al
(2009) J Lipid Res, 50, S9-14] and Masada Disenhouse for help in
adopting to the tutorial format.
Edward A. Dennis
September, 2010
La Jolla, California
E.A. DENNIS 2010 ©