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* Graduate Program in Nutrition and Department of Nutrition, The Pennsylvania State University, University Park, PA 16802
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • aging • vitamin A • lecithin • retinol acyltransferase • cellular retinol-binding protein • retinyl esters • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The
mobilization of retinol is a complex process, involving hydrolysis of
retinyl esters (Harrison 1993
), the transfer of retinol
to hepatocytes and binding of retinol to its transport protein,
retinol-binding protein (RBP) (Soprano and Blaner 1994
), which delivers retinol to peripheral tissues for further
metabolism (Blaner and Olson 1994
). Many of the
biological activities of VA are mediated by its metabolites,
all-trans- and 9-cis-retinoic acid, which
function as the ligands for two families of nuclear retinoid receptors,
the retinoic acid and retinoic X receptors, respectively, that
regulate the transcription of numerous, functionally diverse genes
(Chambon 1996
).
The microsomal enzyme lecithin:retinol acyltransferase (LRAT) is
present in several tissues including liver (MacDonald and Ong 1988b
, Ong et al. 1988
, Randolph et al. 1991
), intestinal mucosa (MacDonald and Ong 1988a
, Ong et al. 1987
), testis
(Shingleton et al. 1989
) and retinal pigment epithelium
(Saari and Bredberg 1989
). LRAT catalyzes the transfer
of a fatty acid from the sn-1 position of
membrane-associated lecithin to retinol that is bound to the
cellular (cytosolic) retinol-binding protein (CRBP) (Ong et al. 1988
, Randolph et al. 1991
, Saari and Bredberg 1989
). LRAT activity as assayed in vitro in liver
homogenates has been shown to be well correlated with the in vivo
esterification of retinol and hepatic storage of
[3H]-VA (Matsuura et al. 1997
).
Although LRAT activity has been measured in a number of tissues, only
liver LRAT activity has been shown to be strongly regulated by the VA
status of the animal. Previous investigations of LRAT activity during
the onset of VA deficiency showed that hepatic LRAT activity declined
progressively, becoming undetectable by the time that liver was
depleted of VA (Randolph and Ross 1991
), whereas
intestinal LRAT activity did not change significantly. Hepatic LRAT
activity was lower in nursling rat pups whose mothers were fed a diet
low in VA than in those nursed by control dams (Gardner and Ross 1993
). It is likely that the natural regulator of LRAT is
all-trans-retinoic acid because this VA metabolite, as well
as certain synthetic analogs of retinoic acid that activate the
retinoic acid nuclear retinoid receptor, is capable of rapidly inducing
LRAT activity in liver of VA-deficient rats (Matsuura et al. 1996
and 1997
). No studies have yet addressed whether LRAT
activity is regulated across the broad range of dietary VA intakes that
may be considered most physiologic in humans, or whether aging results
in changes in LRAT activity and/or the capacity of the liver to store
VA.
Human VA status is determined by long-term patterns of VA
consumption, which can vary widely. For purposes of generalization, VA
intakes may be categorized as deficient, marginal, adequate, excessive
and toxic. The extremes of VA deficiency and toxicity have been the
focus of numerous case studies and have been reproduced in animal
models. However, VA consumption in humans is much more likely to fall
within the range spanning from marginal to excessive, wherein clinical
signs are generally lacking. Relatively little is known of the
regulation of VA metabolism within the range of marginal to excessive
VA intake. Marginal VA deficiency is most likely to occur in young
children (Sommer and West 1996
), pregnant and lactating
women (Sommer and West 1996
, West et al. 1999
), and the elderly, who may consume limited quantities of
yellow and green vegetables, milk and organ meats. For example, in a
probability sample of elderly in Massachusetts, people in the lowest
and second quartiles consumed <0.8 and 0.8–1.4 servings/d,
respectively, of fruits and vegetables high in ß-carotene
(Gaziano et al. 1995
). On the other hand, vitamin and
mineral supplements are widely used in U.S. populations (Kim et al. 1993
, Park et al. 1991
). An excessive intake
of VA may result from chronic consumption of supplements or foods, such
as liver, that contain high concentrations of preformed VA
(Kowalski et al. 1994
). A significant proportion of the
U.S. elderly population report regularly consuming preformed VA from
supplements and diet in amounts equal to 5- to 10-fold above the
Recommended Dietary Allowance (Hartz et al. 1988
).
There is as yet no means to assess hepatic LRAT activity in human
dietary studies. However, studies in appropriate animal models should
shed light on the capacity of the liver to store VA and determine
whether aging is associated with changes in the expression of
retinoid-binding proteins and enzymatic activities involved in the
metabolism of VA. We have used a rat model of aging (Dawson et al. 1999
), which was developed to study systematically the
effects of long-term VA status on immunologic (Dawson et al. 1999
, Dawson and Ross 1999
) and hepatic
functions. The results presented here illustrate that the capacity for
hepatic retinol esterification by LRAT is closely regulated within a
broad yet physiologic range of VA intake, and is well maintained
throughout life.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animal procedures were approved by the Institutional Animal Use and
Care Committee of the Pennsylvania State University. The animals
reported here were part of a larger study (Dawson et al. 1999
) to examine the effects of VA and age on plasma proteins,
liver retinoid metabolism and immune functions. A full description of
the diets, protocols, physical findings and plasma biochemistry (total
proteins, albumin, cholesterol, triglycerides, bilirubin and
alanine:aspartate aminotransferase) used can be found in Dawson et al. (1999)
. Liver functions were studied in an unbiased
sample of 54 rats (the first six replicates of a blocked study with one
rat from each treatment group per block (n = 6 rats
each from 9 treatment groups). Briefly, male Lewis rats, 5–7 d old,
were purchased with lactating dams; upon arrival, they were fed a
semipurified VA-free diet (Dawson et al. 1999
) to
reduce the transfer of VA from mothers to pups during lactation. All
rats had free access to drinking water and diet throughout the study.
After weaning (21 d of age), all groups were fed the AIN-93M diet
(Reeves et al. 1993
), modified to contain one of three
levels of dietary VA [0.35, 4.0 or 25 mg retinol equivalents (RE)/kg
diet] until rats reached the ages of 2–3, 8–10 or 18–20 mo. Rats in
the various age groups were introduced into the study at three times
(first those that would become the old cohort, followed by the
middle-aged and young cohorts) so that dependent variables could be
determined simultaneously for all groups at the end of the study. As a
validation of equivalent VA status longitudinally, plasma retinol was
measured at 3 and 9 mo in the old cohort and at 3 mo in the
middle-aged cohort; these retinol concentrations did not differ
from the concentrations in the young and middle-aged cohorts,
respectively, at the end of the study (data not shown). At the end of
the study, rat were killed individually by asphyxiation with carbon
dioxide, weighed and blood was collected into heparinized syringes from
the abdominal vena cava. The liver was removed, weighed and portions
from each lobe were frozen in plastic vials in liquid nitrogen for
storage at -80°C for later analysis. Other portions of fresh liver
were placed in cold buffer for homogenization for the LRAT assay
described below. Plasma was prepared by centrifugation at 800 x
g for 20 min at 4°C (Dawson et al. 1999
)
and stored at -80°C before retinol analysis.
Liver total lipid, liver and plasma retinol concentration and liver morphology.
For liver total lipid analysis, three pools for each treatment were
prepared by combining equal weights of liver from two rats in each
treatment group. Total lipids were extracted from liver using 20 vol of
chloroform/methanol (2:1, v/v). Aliquots of each lipid extract were
pipetted into weighed glass vials and the solvent was evaporated to
dryness, after which the total weight of each lipid residue was
measured gravimetrically. Another aliquot of the lipid extract was
saponified, an internal standard of trimethylmethoxyphenyl retinol,
obtained from Hoffmann-La Roche (Basel, Switzerland), was added,
and total retinol mass was determined by HPLC with detection at 325 nm
(Ross 1986
). Plasma from each rat was saponified and
total retinol was quantified by the same procedure (Ross 1986
). Plasma retinyl esters were determined by HPLC on
representative samples from each diet group.
CRBP and RBP analysis.
CRBP and RBP mRNA were measured by Northern blot analysis and
slot-blot hybridization. ß-Actin mRNA was measured as control.
Total RNA was extracted from liver using guanidine thiocyanate
(Zolfaghari et al. 1993a
). Northern blot analysis was
used to ensure the presence of a single CRBP or RBP mRNA band and
slot-blot hybridization was used to quantify individual samples.
For this, total RNA (10 µg) was applied to nylon membrane and
hybridized with either a rat CRBP cDNA probe (Rajan et al. 1990
) or a rat RBP cDNA probe (Soprano et al. 1986
) which were labeled with [
-32P]dCTP by
the random primer method (Zolfaghari et al. 1993b
). The
CRBP, RBP or ß-actin mRNA was quantified by densitometry (NIH Image
1.56 program).
For detection of CRBP protein, a pool of liver homogenate was prepared
for each treatment group by combining equal aliquots of the homogenates
from the six livers in each group; a postnuclear supernatant was then
prepared from each pool by centrifugation at 120 x g for 10
min at 4°C (Harrison et al. 1987
). Total protein (40
µg) was loaded per lane on a nondenaturing 10%
polyacrylamide gel and proteins were separated by electrophoresis.
After transfer to a nitrocellulose membrane, CRBP was detected using
rabbit anti-rat CRBP antiserum as described previously
(Randolph et al. 1991
). CRBP was visualized by
chemiluminescence (ECL, Amersham, Arlington Heights, IL) according to
the manufacturer’s instructions. Immunoblots were standardized by
including a known quantity (10 ng) of purified rat liver CRBP on the
same blot. The results were compared using scanning densitometry as
above.
Plasma RBP was quantified by a sensitive and specific RIA, as described
previously, using rat RBP as a standard (Smith et al. 1975
).
LRAT assay.
Fresh rat liver from individual rats was homogenized and centrifuged as
previously described (Matsuura et al. 1996
). LRAT
activity was measured as previously described (Matsuura et al. 1996
, Randolph and Ross 1991
) using purified rat
liver [3H]retinol-CRBP as substrate. Briefly, aliquots of
liver postnuclear supernatants, or boiled samples used as background,
containing 300 µg of total protein were incubated in
duplicate with [3H]retinol-CRBP (5
µmol/L final concentration) at 37°C for 4 min in
0.15 mol/L K2HPO4 buffer, pH 7.4, containing 2
mmol/L dithiothreitol (Matsuura and Ross 1993
). The
esterified [3H]retinol product was separated on columns
of aluminum oxide (Ross 1982
). The specific activity of
LRAT in the postnuclear supernatant was determined as pmol of
3H-retinyl ester formed/(min·mg of protein).
Statistical methods.
Results are presented as means ± SEM for the number
of rats or samples reported. Statistical comparisons were made using a
two-factor ANOVA program (SuperANOVA, Abacus, Berkeley, CA).
Two-way ANOVA tests with significant F-tests for
main effects and interactions were further analyzed by the
Tukey-Kramer test and least-squares means test (SuperANOVA) as
previously described (Dawson et al. 1999
).
P-values <0.05 were considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Body weight (Table 1
) was affected by VA intake and age (P < 0.001 and
P < 0.0001, respectively, two-way ANOVA). Liver
weight (Table 1)
also differed due to both VA intake and age
(P < 0.0001 for each). However, when liver weight was
expressed as a percentage of body weight, VA intake was no longer a
factor (P = 0.14). The weights of several other organs
(brain, kidney, thymus and testis, not shown) were not affected by VA
although, as expected, they differed significantly with age
(P < 0.001).
|
Liver total lipid concentration differed due to both VA intake and age
(P < 0.01 and P < 0.0001,
respectively, two-way ANOVA). Liver lipids were elevated by middle
age in VA-supplemented rats and remained elevated in old rats
(Table 2
).
|
. In rats fed the control diet throughout
their lives, liver total retinol increased gradually with age; the
accumulation of total retinol was approximately proportional to the
months of exposure to diet. For supplemented rats, liver total retinol
was very high, averaging >7 µmol/g (>2000
µg/g) by 2–3 mo of age. Total retinol doubled to >14
µmol/g in liver of middle-aged rats and increased
again to >19 µmol/g in old rats. Thus, the rate of total
retinol accumulation slowed in VA-supplemented rats between middle
and old age. Plasma retinol to RBP molar ratio.
The molar ratio of plasma retinol to RBP is known to be correlated with
VA status, i.e., it is low in VA deficiency and elevated in
hypervitaminosis A and VA toxicity. The saturation of plasma RBP with
retinol (molar ratio of total retinol:RBP) in the three diet groups
during aging is shown in Figure 1
. For VA-marginal and control rats, the molar ratio was <1 at all
ages. In contrast, all VA-supplemented rats had molar ratios >1,
which increased steadily with age. Plasma retinyl esters were detected
only when the plasma total retinol: RBP molar ratio was >1 (data not
shown).
|
There were relatively small but significant differences due to VA and
age in the levels of CRBP and RBP mRNA (Table 3
). ß-Actin, measured as a control, did not differ with VA or age. CRBP
mRNA expression increased with age and was higher in
VA-supplemented rats. CRBP protein, detected by immunoblot analysis
in pooled liver homogenates, was slightly higher in old,
VA-supplemented rats than in other groups (data not shown). RBP
mRNA expression declined with old age in all diet groups.
|
Liver LRAT activity differed significantly with VA intake (P
< 0.0001, two-way ANOVA). Although there was no significant
main effect of age (P = 0.47), there was a significant
interaction between VA and age (P < 0.0001) because
LRAT activity declined with age in VA-marginal rats and increased
in VA-supplemented rats (Fig. 2
).
|
). VA intake was a significant determinant of plasma total retinol
concentration (P < 0.0001) (Dawson et al. 1999
). Although there was a significant correlation between
liver LRAT specific activity and plasma total retinol concentration
(r = 0.633, P < 0.0001), the data more
closely fit a sigmoidal curve, as is illustrated in Figure 3
.
Differences in liver LRAT specific activity were greatest between
plasma total retinol concentrations of ~0.3 and 1.8
µmol/L. LRAT activity was also correlated with plasma RBP
(r = 0.327, P = 0.0372).
|
|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Neither VA deficiency nor VA
toxicity developed, as evidenced by normal rates of growth in
VA-marginal and VA-supplemented rats compared with control rats
and normal values for indicators of hepatic function (plasma
alanine:aspartate aminotransferase activity and bilirubin
concentration) in all groups (Dawson et al. 1999
).
Marginal VA status was indicated by minimal liver VA stores (Table 2)
,
low plasma retinol (Fig. 3)
and a plasma total retinol:RBP molar ratio
of <1. VA status in the excessive range was indicated by liver VA
concentrations that were ~10- to 20-fold greater than those of
control rats (Table 2)
, elevated plasma total retinol (Fig. 3)
, a total
retinol:RBP ratio >1 and moderately fatty liver (Table 2)
. The
accumulation of fat in rat liver has been reported to be a consequence
of short-term hypervitaminosis A (Mallia et al. 1975
). Chronic VA supplementation in our model had no
significant effect on liver lipids in young rats (Table 2)
, but total
lipids increased by middle age. By old age, liver lipids were higher in
rats fed either the control or VA-supplemented diet throughout
their lives, whereas rats fed the VA-marginal diet were somewhat
protected from this increase in total fat (P < 0.05
vs. control and supplemented groups).
Consumption of the VA-supplemented diet was associated with a molar
ratio of total retinol:RBP >1. Retinyl esters were confirmed in the
plasma of VA-supplemented rats but were not detected in control or
VA-marginal rats. High levels of circulating retinyl esters and a
molar ratio of total retinol:RBP >1 are generally taken as signs of
hypervitaminosis A (Smith and Goodman 1976
). Yet, as
noted above, plasma alanine:aspartate aminotransferase and bilirubin,
which were assayed as tests of possible liver damage, did not differ
among treatment groups in our study (Dawson et al. 1999
)
and were within the 90% confidence intervals previously reported for
normal rats (Wolford et al. 1986
). Several human studies
in vitamin supplement users have looked for a relationship between
plasma retinyl esters and indicators of liver function, but no clear
relationship has emerged. Stauber et al. (1991)
studied
a sample of healthy New Mexican subjects >60 y old. In these subjects,
intake of supplemental + dietary VA was highly correlated with plasma
retinyl esters, but there was no relationship between plasma retinyl
esters and several liver function tests except for plasma
alanine:aspartate aminotransferase (r = 0.34,
P < 0.0002). Other investigators have looked for
adverse clinical signs and biochemical changes in adults receiving
supplements of 
25,000 IU (7500 RE)/d
(Cartmel et al. 1999
, Redlich et al. 1999
, Sibulesky et al. 1999
). Most of these
studies reported a modest increase in plasma retinol, retinyl esters
and sometimes lipids, but none reported adverse clinical symptoms or
signs of liver toxicity attributable to VA. Krasinski et al. (1989)
reported elevated plasma retinyl esters in users of
VA-containing supplements, with higher levels in the elderly and
those using supplements for 
5 y. Elderly subjects with retinyl esters
380 nmol/L were more likely to have elevated plasma alanine:aspartate
aminotransferase activity. However, it is not known whether these
relationships are of a causal nature and are indicative of liver
impairment. The plasma retinyl ester levels reported by these authors
(Krasinski et al. 1989
, Stauber et al. 1991
) were much lower than those reported for frank VA toxicity
(Smith and Goodman 1976
). It is noteworthy that
VA-supplemented rats in our study had elevated levels of plasma
retinyl esters (and a molar ratio of total retinol:RBP >1) throughout
their lives, but still maintained normal indices of liver function and
appeared to be in good health.
A main goal of creating an animal model of varied VA status during
aging was to study biochemical parameters, such as liver VA storage,
CRBP expression and LRAT activity, under conditions that may model the
VA status in humans who regularly consume diets low in total VA or high
in preformed retinol. The process of retinol esterification by LRAT
utilizes retinol bound to CRBP, a cytosolic protein with one binding
site for a molecule of retinoid (Levin et al. 1988
,
Ong et al. 1994
). The promoter region of the CRBP gene
contains a retinoic acid response element (Ong et al. 1994
), and thus could be responsive to changes in retinoic acid
concentration. However, in short-term models of VA deficiency or
excess, CRBP protein was reduced only modestly in liver of
VA-deficient rats and did not differ significantly in rats fed
excess retinol (Kato et al. 1985
). Although we observed
significant differences in CRBP mRNA due to diet and age (Table 3)
,
none of the mean values differed by >7% from the young control group,
which was chosen as the reference group. With this modest variation, it
seems unlikely that the level of CRBP expression is an important
determinant of the liver’s capacity to esterify retinol.
Previous studies in young rats have demonstrated that hepatic LRAT
activity is regulated by VA deficiency and acute retinoid treatment
(Gardner and Ross 1993
, Matsuura and Ross 1993
, Randolph and Ross 1991
); however, no
previous studies have addressed the regulation of retinol
esterification by LRAT in a chronic dietary model maintained across the
life span. LRAT activity as assayed in vitro has been shown to be well
correlated with retinol esterification in liver of intact rats
(Matsuura et al. 1996
). It is important to note that a
saturating concentration of CRBP-bound retinol was used to assay
LRAT activity in this and previous studies (Matsuura et al. 1996
) so that the quantity of substrate was not rate limiting.
In this model of VA status during aging, hepatic LRAT activity was
strongly regulated by the VA status of the rats (Fig. 3)
over the wide
but physiologically relevant range of VA intakes from marginal to
excessive. Together with previous studies, these data indicate that
LRAT activity varies over a wide continuum, ranging from undetectable
in VA deficiency (Randolph and Ross 1991
), to minimal
(marginal VA status, Fig. 2
, 3
), and increasing until VA sufficiency
(control status) is reached. A plateau in hepatic LRAT activity was
observed when plasma retinol concentrations reached ~1.8
µmol/L (Fig. 3)
. Interestingly, analysis by HPLC confirmed
that plasma total retinol in excess of ~1.6–1.8 µmol/L
was due to the presence of retinyl esters, which are known to be
carried by plasma lipoproteins (Smith and Goodman 1976
).
Thus, LRAT activity actually varied nearly continuously over the range
of plasma unesterified retinol from ~0.3 to 1.8 µmol/L,
which is associated with RBP, but did not change in the range in which
plasma retinyl esters occur (e.g., total retinol concentrations above
~1.8 µmol/L). It is not understood how plasma retinol concentration
might regulate liver LRAT activity. As noted previously, it is likely
that the VA metabolite, retinoic acid, regulates LRAT activity. Plasma
retinol recycles to liver several times before its irreversible
degradation (Kent et al. 1976
); thus it is possible that
retinol flux into liver and its metabolism to retinoic acid occur in
proportion to plasma retinol concentration and thus provide a
quantitatively variable signal for the regulation of hepatic LRAT.
In human adults, plasma retinol levels <0.7 µmol/L (<20
µg/dL) have been interpreted as an indicator of increased
likelihood of physiologic impairment (Life Science Research Office 1985
). In the National Health and Nutrition Examination
Survey-I, the 5th, 50th and 90th percentiles for serum VA in young
adult men were in the ranges of 25–29, 50–54 and 85–89
µg/dL (~0.9–3.0 µmol/L), respectively
(Life Science Research Office 1985
). Therefore, the
lower half of plasma retinol concentrations that are prevalent in the
U.S. fall within the middle to upper range (1–1.8 µmol/L)
of the plasma retinol concentrations that were associated with the
regulation of hepatic LRAT activity in our rat model (Fig. 3)
. Although
it is thought that plasma retinol is not very sensitive to VA intake
within the range of marginal to excessive dietary VA, effects of diet
or supplements have been noted in some studies. For example, in a
longitudinal study of elderly New Mexico residents, men who consumed a
vitamin-mineral supplement averaging ~2000 RE/d had higher plasma
retinol concentrations than men not taking a supplement (Garry et al. 1987
). If liver LRAT in humans is regulated similarly to
rat liver LRAT, it is likely that hepatic retinol esterification is
regulated within the range of serum or plasma VA concentrations that
are prevalent in the U.S. population and may respond to changes in the
quantity of VA consumed via diet + supplements. This model would
predict that, in individuals whose VA status is marginal or deficient,
hepatic LRAT activity would be greatly reduced. The down-regulation
of hepatic LRAT activity may be a homeostatic mechanism that serves to
preserve retinol for other essential processes, such as holo-RBP
formation and secretion, and/or the synthesis of bioactive retinoids
such as retinoic acid.
|
FOOTNOTES |
|---|
2 The first two authors contributed equally to
this work.
4 Abbreviations used: CRBP, cellular
retinol-binding protein; LRAT, lecithin:retinol acyltransferase;
RBP, retinol-binding protein; RE, retinol equivalents; VA, vitamin
A.
Manuscript received November 19, 1999. Initial review completed January 21, 2000. Revision accepted February 18, 2000.
|
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