Metabolic events in the liver

Esterifi cation of retinol
Within hepatic stellate cells, retinol binds to CRBPI
which directs retinol to LRAT for esterifi cation
when the vitamin is present in normal amounts.
When retinol is present at high levels and the pool
of CRBP-I becomes saturated, ARAT may esterify the
excess. Thus, as in the intestine, both enzymes may be
involved in hepatic retinol esterifi cation, depending
on the amount of retinol present and on whether it is
bound to CRBP-I.
Storage of retinyl esters
Vitamin A is unique among vitamins because it is
massively stored by the liver. The level of stored retinyl
ester fl uctuates in accordance with dietary intake.
Normally, most of the newly absorbed retinol is transferred
within 2–4 hours from hepatocytes to stellate
cells for storage. However, during periods of vitamin
A insuffi ciency, newly absorbed retinol is secreted
from hepatocytes, as holoRBP, directly into the blood
to satisfy the immediate needs of the tissues.
The transfer of newly absorbed retinol from
hepatocytes to stellate cells within the liver is mediated
by RBP, thus other components of chylomicron
remnants, such as cholesterol and vitamin D, are not
transferred. Binding of retinol to RBP in hepatocytes
initiates a translocation of holoRBP from the endoplasmic
reticulum to the Golgi apparatus, followed
by secretion of the retinol complex from the cell.
Within stellate cells, retinol is esterifi ed and the esters
are stored in cytoplasmic lipid droplets. The storage
capacity of hepatic stellate cells is high and accounts
for about 50 to 80% of the total body pool of vitamin
A. The normal reserve of vitamin A in stellate cells is
adequate to last for several months in humans. Stellate
cells are also found in the intestine, kidney, heart,
large blood vessels, ovaries and testes; these cells store
retinyl esters when large amounts of vitamin A are
consumed. When the stellate cells contain so much
retinol that they can accept no more, hypervitaminosis
A occurs.
The amount of vitamin A stored in the liver infl uences
retinol utilization by extrahepatic tissues, and
therefore hepatic liver reserves are a true indication
of vitamin A status. Green et al. (1987) determined
the retinol utilization rate in rats provided with different
intakes of vitamin A, such that the rats had low,
marginal or high liver vitamin A reserves. Vitamin Adepleted
rats exhibited a lower utilization rate, which
was positively correlated with the size of the plasma
retinol pool; i.e. the lower the plasma retinol concentration,
the lower the vitamin A utilization rate. The
increased rate of utilization observed in rats of higher
vitamin A status was refl ected in an increased rate of
retinol catabolism. It appeared that some minimal
utilization rate is maintained as long as dietary supply
and/or liver stores of vitamin A can maintain normal
plasma retinol concentrations. The decreased utilization
rate in depleted states could be a way of conserving
vitamin A for its most critical functions, whereas
in vitamin A suffi ciency increased catabolism prevents
excessive accumulation of retinol. Accelerated
catabolism as a function of increase in liver vitamin A
stores was also reported in rats fed excessive amounts
of vitamin A (Leo et al., 1989).
Mobilization of retinol
The vitamin A stored in stellate cells can be readily
mobilized for use in a highly regulated process. Thus
an individual’s plasma vitamin A levels remain quite
constant over a wide range of dietary intakes and liver
stores. Only when liver reserves of vitamin A are nearly
depleted do plasma concentrations of retinol decrease
signifi cantly. A kinetic model of retinol dynamics in
rats (Green et al., 1993) predicted that the stellate cell
retinol pool responsible for the secretion is small and
rapidly turning over. This is compatible with the relatively
small amounts of apoRBP observed in stellate
cells (more than 90% of the apoRBP in liver is found
in hepatocytes). Upon demand, the retinyl esters are
hydrolysed to retinol, which then combines with RBP
to form holoRBP. This complex is secreted into the
bloodstream where it becomes reversibly complexed
in a 1:1 molar ratio with transthyretin. The formation
of the larger retinol–RBP–transthyretin complex
minimizes the loss of holoRBP in the urine during its
passage through the kidney.
One factor that specifi cally regulates the release of
holoRBP from the liver is the dietary intake of vitamin
A. Studies in the rat (Muto et al., 1972; Smith et
al., 1973) showed that in the retinol-depleted state,
the secretion of holoRBP from the liver was blocked,
resulting in the accumulation of an enlarged pool
of apoRBP in the liver and a concomitant decline
in plasma RBP levels (as holoRBP–transthyretin).
Oral administration of retinyl acetate to the depleted
Vitamin A: retinoids and carotenoids 143
rats stimulated the rapid secretion of holoRBP from
the expanded liver pool into the plasma and within
5 hours after administration the plasma RBP levels
had returned to normal. This effect of retinol upon
RBP secretion took place without affecting RBP
synthesis (Soprano et al., 1982); this is unusual as the
synthesis of other binding proteins (e.g. transferrin,
ferritin and zinc metallothionein) is controlled by
their specifi c ligands. These experiments demonstrated
that the livers of vitamin A-defi cient animals
contain a pool of previously formed apoRBP, which
can be released rapidly into the plasma, as holoRBP,
as soon as vitamin A becomes available. The delayed
(5 h) response to oral administration of vitamin A is
due to the processes of intestinal absorption, hepatic
uptake of chylomicron remnant retinyl ester, and hydrolysis
of ester to provide retinol.