Vitamin A metabolism

Domina Petric, MD
Vitamin A: metabolism

Absorption of vitamin A
I.
4/7/2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.

Absorption of retinoids
• Most of the preformed vitamin A in the
diet is in the form of retinyl esters.
• Retinyl esters are hydrolyzed in the
lumen of the small intestine to yield
retinol.
• This step is catalyzed by hydrolases
produced by the pancreas and situated
on the mucosal brush border or intrinsic
to the brush border itself.
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• The retinyl esters, as well as the carotenoids,
are hydrophobic and, thus, depend on
micellar solubilization for their dispersion in
the aqueous environment of the small
intestinal lumen.
• Vitamin A is poorly utilized from low-fat diets!
• The micellar solubilization of vitamin A
facilitates access of soluble hydrolytic
enzymes to their substrates.
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The overall absorption of retinol from retinyl
esters appears to be fairly high (about 75%).
This process appears to be minimally affected by
the level and type of dietary fat, although the
absorption is appreciably less efficient at very
high vitamin A doses .
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Vitamin A can also be absorbed via non
lymphatic pathways.
In mammals, the portal system may be an
important alternative route of vitamin A
absorption when the normal lymphatic pathway
is blocked.
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Absorption of carotenoids
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Carotenoid metabolism linked
to absorption
• Some carotenoids can be provitamins A because they
can be metabolized to yield retinal due to the action
of retinal-forming carotene dioxygenases.
• Most of this bioconversion occurs via the central
cleavage of the polyene moiety by a predominantly
cytosolic enzyme, β-carotene 15,15′-dioxygenase, found
in the intestinal mucosa, liver and corpus luteum.
• The enzyme requires iron as a cofactor.
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Retinoid metabolism linked to
absorption
• Retinal produced by at least the central cleavage step
is reduced in the intestinal mucosa to retinol.
• This step is catalyzed by another enzyme, retinaldehyde
reductase, which is also found in the liver and eye.
• The reduction requires a reduced pyridine nucleotide
(NADH/NADPH) as a cofactor.
• This step can be catalyzed by a short-chain alcohol
dehydrogenase/aldehyde reductase.
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Mucosal metabolism of retinol
• Retinol, formed either from the hydrolysis of
dietary retinyl esters or from the reduction of
retinal cleaved from β-carotene, is absorbed
by facilitated diffusion via a specific
transporter.
• Then, retinol is quickly re-esterified with long-
chain fatty acids in the intestinal mucosa.
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Mucosal metabolism of retinol
• Vitamin A is transported to the liver mainly (80 to 90% of
a retinol dose) in the form of retinyl esters.
• The composition of lymph retinyl esters is independent
of the fatty acid composition of the most recent meal.
• Retinyl palmitate typically comprises about half of the
total esters.
• Retinyl stearate comprises about a quarter.
• Retinyl oleate and retinyl linoleate are present in small
amounts.
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Two pathways for the enzymatic reesterification of
retinol are:
A low-affinity route involves uncomplexed retinol.
• It is catalyzed by acyl-CoA: retinol
acyltransferase.
A high-affinity route involves retinol complexed
with a specific binding protein, cellular retinol-
binding protein type II.
• It is catalyzed by lecithin–retinol acyltransferase.
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Vitamin A transport
II.
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Retinyl esters
Retinyl esters are secreted from the
intestinal mucosal cells in the hydrophobic
cores of chylomicron particles, by which
absorbed vitamin A is transported to the
liver through the lymphatic circulation,
ultimately entering the plasma
compartment through the thoracic duct.
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Transport of carotenoids
Carotenoids that are not
metabolized at the intestinal mucosa
are transported from that organ by
chylomicra via the lymphatic
circulation to the liver, where they
are transferred to lipoproteins.
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The hydrocarbon carotenoids are
transported primarily in low-density
lipoproteins (LDLs).
The more polar carotenoids are transported
in a more evenly distributed manner among
LDLs and high-density lipoproteins (HDLs).
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β-carotene is retained by the
chylomicron remnants to be
internalized by the liver for
subsequent secretion in very low
density lipoproteins (VLDLs).
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Impact of abetalipoproteinemia
• The absorption of vitamin A (as well as the other fat soluble
vitamins) is a particular problem in patients
with abetalipoproteinemia.
• These patients lack apo B and can not synthesize any of the
apo B-containing lipoproteins: LDLs, VLDLs, chylomicra.
• Having no chylomicra, they show hypolipidemia and low
plasma vitamin A levels.
• When given oral vitamin A supplementation, their plasma
levels are normal.
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Storage of vitamin A in the liver
• Newly absorbed retinyl esters are taken up by the
liver in association with chylomicron remnants by
receptor-mediated endocytosis on the part of liver
parenchymal cells.
• Within those cells, remnants are degraded by
lysosomal enzymes.
• Retinol can be transferred from the parenchymal
cells to stellate cells, where it is re-esterified.
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Retinyl ester hydrolysis
• Vitamin A is mobilized as retinol from the liver by
hydrolysis of hepatic retinyl esters.
• This mobilization accounts for about 55% of the
retinol discharged to the plasma (the balance
comes from recycling from extrahepatic tissues).
• The retinyl ester hydrolase involved in this
process shows extreme variation between
individuals.
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Retinol-binding protein
Once mobilized from liver
stores, retinol is transported to
peripheral tissues by means of a
specific carrier protein, plasma
retinol-binding protein (RBP).
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Transport of retinoids
The transport, storage, and
metabolism of the retinoids involve
their binding to several other binding
proteins, such as cellular retinol-
binding protein types I and II, and
cellular retinoic acid-binding protein
types I and II.
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Cellular uptake of retinol
• Due to their hydrophobic character, the
plasma membranes do not present a barrier
to retinol uptake.
• Retinol can enter target cells by nonspecific
partitioning into the plasma membrane from
RBP, but most of the vitamin appears to enter
cells through specific RBP (receptor-mediated
mechanisms).
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Retinol recycling
The majority of retinol
that leaves the plasma
appears to be recycled.
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Plasma retinol homeostasis
In healthy individuals,
plasma retinol is maintained
within a narrow range:
40–50 mg/ml in adults.
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Vitamin A in adipose tissue
Appreciable amounts
of vitamin A are stored
in adipocytes: 15–20%
of total body store.
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Milk retinol
Retinol is transferred
from mother to
infant through milk.
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Metabolism of vitamin A
III.
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Metabolism of vitamin A
The metabolism of vitamin A centers
around the transport form, retinol, and the
various routes of conversion available to it:
•esterification
•conjugation
•oxidation
•isomerization
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Excretion of vitamin A
IV.
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Excretion of vitamin A
• Vitamin A is excreted in various forms in
both the urine and feces.
• Under normal physiological conditions,
the efficiency of enteric absorption of
vitamin A is high (80–95%), with 30–60%
of the absorbed amount being deposited
in esterified form in the liver.
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• Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
Literature
4/7/2018

Vitamin A metabolism

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