Absorption, transport and metabolism

Retinol in the free state can enter the lipid bilayer of
biological membranes and disrupt membrane structure
and function. In order to permit transport within
an aqueous environment and to limit its level in membranes,
retinol (and other retinoids) are bound to
proteins, both extracellularly and intracellularly. The
intracellular retinol–protein complex is the metabolically
active form of retinol. Alternatively, retinol is
esterifi ed with long-chain fatty acids for transport in
lipoproteins or storage in cytoplasmic lipid droplets.
Protein binding and esterifi cation prevent the disruptive
action of free retinol on membrane structure and
function, whilst also protecting retinoids from unwanted
metabolic processing and decomposition.
In the human, the main events that take place
from absorption of dietary vitamin A to cellular metabolism
in the target tissues are as follows. Ingested
retinyl esters and carotenoids are incorporated into
mixed micelles in the intestinal lumen and the retinyl
esters are hydrolysed. The micelles dissociate and the
retinol and carotenoids are absorbed. Within the
enterocytes, varying proportions of the provitamin
carotenoids are converted fi rst to retinaldehyde and
then to retinol, which is subsequently esterifi ed. Some
of the retinaldehyde is oxidized irreversibly to retinoic
acid. Retinoic acid can also be produced from β-carotene
via apo-carotenals of varying chain length without
involving retinaldehyde as an intermediate. The
absorbed retinol is also esterifi ed and the combined
retinyl esters, accompanied by varying small amounts
of unchanged carotenoids, are released into the
bloodstream via the lymphatic system as components
of chylomicrons. The absorption of β-carotene and
retinyl ester and principal metabolic events within the
enterocyte are shown diagrammatically in Fig. 7.3.
The circulating chylomicrons undergo lipolysis
and the resultant chylomicron remnants are taken
up by the liver and to a lesser extent by extrahepatic tissues. Within the liver the chylomicron remnant
retinyl esters are hydrolysed and most of the retinol
is transferred from hepatocytes to stellate cells where
it is esterifi ed and stored. Remnant carotenoids do
not accumulate in liver cells: they are released into
the circulation as components of very low density
lipoproteins (VLDLs) and ultimately stored intact
in adipose tissues and in various organs of the body.
Upon demand, the retinyl esters in the liver are hydrolysed
and the retinol is released into the bloodstream
bound to retinol-binding protein (RBP), which is
synthesized in the liver. In the plasma the retinol–RBP
complex forms a larger complex with a protein called
transthyretin (formerly known as prealbumin), which
also transports thyroid hormone. The retinol–RBP–
transthyretin complex delivers retinol to a cell-surface
receptor expressed in vitamin A-requiring cells. RBP
is recognized by the receptor and, after negotiating
the lipid bilayer of the plasma membrane, the retinol
interacts with a specifi c cellular binding protein. Cytoplasmic
retinol is subject to a variety of metabolic
fates, including oxidation to retinoic acid. Cellular
binding proteins play major roles in controlling retinol
metabolism and may regulate the movement of
retinoic acid to the nucleus where it acts as a hormone
to affect gene expression.