Department of Nutrition, School of Food and Nutritional Sciences, The University of Shizuoka, Shizuoka 422, Japan
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ABSTRACT |
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We previously found
that dietary unsaturated fatty acids increase cellular retinol-binding
protein type II (CRBP II) mRNA and its protein levels in rat jejunum.
To obtain insight into mechanisms for its gene induction, we
investigated the effect of depletion of dietary fat on CRBP II mRNA
levels and we further examined whether dietary retinol is necessary for
dietary fat-induced CRBP II gene expression. Feeding the fat-free diet,
which contained a sufficient amount of vitamin A, repressed CRBP II
mRNA accumulation by 50% within 1 day, and this low level was
sustained over the next 9 days. Parallel to the decreased CRBP II mRNA
level, the peroxisomal proliferator-activated receptor- (PPAR-
)
mRNA level in rat jejunum was decreased by long-term (7 days) feeding
of an isocaloric low-fat diet compared with the control. Oral
administration of corn oil in the animals fed vitamin A-free diet
elicited approximately threefold accumulation of CRBP II mRNA within 6 h. However, the administration of 9-cis-retinoic acid brought
about no accumulation of CRBP II mRNA. Even when rats were vitamin
A-deficient, oral administration of corn oil, but not
9-cis-retinoic acid, caused an increase in jejunal CRBP II mRNA
level. These results suggest that CRBP II gene expression in rat
jejunum may be regulated predominantly by dietary fatty acids but
little by dietary retinoids.
corn oil; fat-free diet; messenger ribonucleic acid; vitamin A deficiency; 9-cis-retinoic acid
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INTRODUCTION |
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CELLULAR RETINOL-BINDING protein
type II (CRBP II) is abundantly localized in small intestinal
epithelial cells and plays important roles in intestinal absorption,
cytoprotection, and metabolism of retinol and -carotene.
Retinol absorbed in the enterocytes binds to CRBP II (19), and this
protein-retinol complex serves as a substrate for microsomal
lecithin:retinol acyltransferase (20). Retinal, which is converted from
-carotene, binds to CRBP II, and it is metabolized to
retinol by retinal reductase (10). Thus CRBP II plays functional roles
in the small intestine.
We previously found that jejunal CRBP II mRNA and its protein levels in
rats fed a high-fat (corn oil) diet were more than twofold greater than
in rats fed a low-fat diet (7). Unsaturated fatty acids, e.g., oleic
acid, linoleic acid, and -linolenic acid, enhanced CRBP II mRNA
levels, whereas medium-chain fatty acids and saturated fatty acids had
little effect on CRBP II mRNA levels (24). The increase in CRBP II mRNA
levels induced by the high-fat diet or the unsaturated fatty acids may
be associated with activation of nuclear receptors, e.g., peroxisome
proliferator-activated receptor-
(PPAR-
), which is constitutively
expressed in rat small intestine (24).
The in vitro studies revealed that PPAR- and human retinoid X
receptor (RXR-
) form a heterodimer, which can bind to a 5'-flanking region of mouse CRBP II gene (15). The PPARs and RXRs are known to be
members of the steroid hormone receptor superfamily (9). The mouse CRBP
II gene was found to have a DNA binding site for the nuclear receptors,
termed the retinoid X response element, consisting of the direct
AGGTCA-like motif with one intervening nucleotide, which is called DR-1
(22). Interestingly, a peroxisome proliferator response element,
consisting of an almost perfect direct repeat of the sequence
AGG(T/A)CA spaced by a single base pair, has been identified in the
upstream regulatory sequence of the gene encoding acyl-CoA oxidase (4,
30). Cotransfection of expression plasmids for both PPAR and RXR-
in
the presence of clofibric acid (a peroxisome proliferator) and
9-cis-retinoic acid (9-cis-RA), a ligand for RXRs,
resulted in a synergistic increase in the activity of acyl-CoA oxidase
promoter (15). Furthermore, PPAR-
was shown to be activated not only
by peroxisome proliferators but by unsaturated fatty acids or some
types of prostaglandins as well (13, 31). Therefore, we hypothesized that the CRBP II gene expression might be stimulated by the action of
the PPAR-RXR heterodimer. However, it remained unclear whether the CRBP
II gene expression should be dominated by PPARs activation through a
fatty acid signaling pathway or RXR activation through a retinoid
signaling pathway or both. To answer these questions, we investigated
the effect of a fat-free diet containing an adequate amount of vitamin
A on CRBP II mRNA level in rat jejunum. We also investigated whether
long-term feeding of a low-fat diet was accompanied by a decrease in
PPAR-
mRNA level. Further studies were designed to clarify whether
9-cis-RA would be required for the dietary fat (unsaturated
fatty acids)-induced accumulation of CRBP II mRNA using the
rats fed a vitamin A-depleted diet. We report the results here,
suggesting that the regulation of CRBP II gene expression in rat small
intestine is possibly dominated by dietary fatty acids but not by
dietary retinoids under a physiological condition in intact animals.
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MATERIALS AND METHODS |
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Experimental design and animals. Four studies on CRBP II gene expression were conducted. In the first study (experiment 1), 6-wk-old Wistar male rats (Japan SLC, Hamamatsu, Japan) were prefed the 10% corn-oil diet containing an adequate amount of vitamin A according to the National Research Council recommended requirement (1) for 5 days and then four animals were subjected to the tissue sample collection at the beginning of the experimental period (day 0). The rest of the rats were divided into two groups of 12 rats each. One group of rats (control) had free access to the 10% corn-oil diet. The other group (experimental) of rats received the fat-free diet. The amount of diet for the experimental group was restricted to that of the control group, i.e., pair-feeding was performed. The composition of the diet for prefeeding is shown in Table 1. The fat-free diet was prepared by withdrawing corn oil from the 10% corn-oil diet and substituting it with sucrose. Four animals each from both the control and experimental groups were dissected to collect small intestine, liver, and blood on days 1, 5, and 10 of the experimental period.
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Preparation of tissue sample.
The duodenum extending from the pylorus to the ligament of Treitz was
discarded. The proximal one-half (jejunum) of jejunoileum was flushed
with 10 ml of ice-cold 0.9% NaCl solution, cut along its length, and
blotted with a wet paper. A 1.0-cm (100 mg) segment was excised from
the middle region of the jejunal segment and immediately used for RNA
extraction. Mucosa was scraped from the rest of the jejunal segment
with a glass microscope slide, and it was quickly frozen in liquid
nitrogen and stored at 80°C. The jejunal mucosa was homogenized in
two volumes (vol/wt) of 0.2 M potassium phosphate butter (pH 7.2)
containing 0.25 M sucrose using a Teflon-glass homogenizer. The
homogenates were centrifuged at 10,000 g for 15 min (4°C),
and the resulting supernatants were centrifuged at 105,000 g
for 1 h (4°C). The resulting cytosol fractions were stored at
80°C for measurements of the amount of CRBP II protein.
RNA preparation and Northern blot analysis.
Total RNA isolation from the jejunal segments was performed by the
acidified guanidinium thiocyanate methods as described by Chomczynski
and Sacchi (3). Northern blot hybridizations of CRBP II mRNA and
PPAR- mRNA were carried out using 32P-labeled CRBP II
cDNA and PPAR-
cDNA probes as described previously (7, 24). The
washed membranes were exposed to an image plate (Fuji Film, Tokyo,
Japan). Control hybridization was performed using rat 28S rRNA cDNA.
The rat 28S rRNA cDNA, corresponding to +3646 to +4205 of rat 28S rRNA
(2), was synthesized with RT (Superscript RNase H
;
Bethesda Research Laboratories, Gaithersburg, MD) and random hexamer
(Takara Shuzo, Kyoto, Japan) using 1.0 µg of rat liver total RNA as a
template, according to the procedure described by Kawasaki (12). The
cDNA was amplified and subcloned as described elsewhere (24). CRBP II
mRNA levels were normalized for mRNA abundance in the blots of the
control hybridizations of 28S rRNA.
Immunoblot analysis of CRBP II protein levels in jejunal mucosa. The jejunal cytosol fractions were used for determinations of CRBP II content by Western blot analysis with a monospecific antiserum (26). SDS-PAGE was performed according to Laemmli (16) using 15% acrylamide, 1-mm-thick slab gels. The known amounts of purified rat CRBP II (26) were included in the Western blot analysis as standard. The proteins in the gel were electrophoretically transferred to a nitrocellulose membrane (5 V/cm, 2 h), and immunoblotting was performed by the method of Tsang et al. (29) using rabbit anti-rat CRBP II antiserum (26) and goat anti-rabbit IgG-peroxidase conjugate (Jackson Immunoresearch Laboratories, West Grove, PA) as the primary and the secondary antibodies, respectively. The amount of CRBP II was quantified by densitometric determination using a densitometer (CS-9000, Shimadzu, Kyoto, Japan).
Determination of retinol in serum and liver. Serum retinol concentration was fluorometrically determined by HPLC as described previously (25). Frozen livers were thawed on ice and homogenized in 50 mM Tris · HCl buffer (pH 7.5) containing 0.25 M sucrose, 25 mM MgCl2, 16 mM EDTA, and 40 mM L-ascorbic acid to make 10% liver homogenate. An aliquot of the homogenate was saponified, and total retinol content was determined using an internal standard of retinyl acetate as described previously (27). Serum concentrations of 9-cis-RA and all-trans-RA were determined according to the procedure described by Tang and Russell (28). Serum (1.5 ml) was mixed with 2 ml of ethanol containing 1% pyrogarol and centrifuged for 10 min at 3,000 rpm. The resulting supernatants were mixed with 1 ml of 2 N sodium hydroxide. After 10 min, neutral and basic lipophilic compounds were extracted twice with 3 ml of n-hexane, and the lower aqueous phase was treated for 10 min with 2 ml of 2 N HCl, followed by extraction with 3 ml of n-hexane. The hexane phase was collected and evaporated under nitrogen gas. The residue was dissolved in 50 µl of methanol, and aliquots were analyzed by a reverse phase HPLC using a Shimadzu LC-6A system fitted with a µBondapack C18 column (10 nm particle, 3.9 mm × 25 cm; Waters Associates, Milford, MA). The mobile phase consisted of 80% methanol containing 0.01 M ammonium acetate at a flow rate of 1 ml/min. Absorbance of the retinoids was determined using a spectrophotometer (Shimadzu SPD-6AV) with a wavelength of 350 nm. External standards of 9-cis-RA (Biomol Research Laboratories, Plymouth Meeting, PA) and all-trans-RA (Sigma) were used for quantification of these eluted retinoids.
Statistical analysis. All results were subjected to one-way ANOVA. Differences in mean values among groups were tested using Tukey's multiple range test (23) and were considered statistically significant at P < 0.05.
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RESULTS |
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Effect of fat-free diet on CRBP II mRNA level in rat jejunum. In experiment 1 we examined the time-dependent effect of feeding a fat-free diet. As shown in Fig. 1, consumption of the fat-free diet decreased the CRBP II mRNA level to ~50% of the control group that received the 10% corn-oil diet. This decline occurred within 1 day after introduction of the fat-free diet containing an adequate amount of vitamin A. The CRBP II mRNA level of animals fed the fat-free diet remained low throughout the experimental periods. The amount of CRBP II protein in jejunal cytosol of rats on the final day of the experimental period was determined by Western blot analysis, and relative protein levels were quantified by analyzing the bands densitometrically. The typical bands analyzed were photographed (Fig. 2A), and the relative protein abundance was expressed in arbitrary units (Fig. 2B). The amount of CRBP II in rats fed the fat-free diet for 10 days was 40% less than that in rats fed the 10% corn-oil diet. The liver total retinol content in rats on the final day of the experimental period was assayed. The fat-free diet group showed significantly lower (14%, P < 0.05) hepatic total retinol content (1.55 ± 0.07 mg/liver) than that of the 10% corn oil group (1.79 ± 0.06 mg/liver).
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Effect of long-term feeding of low-fat diet on PPAR-
mRNA level in rat jejunum.
Although our previous study showed that PPAR-
and RXR-
mRNA
levels were unchanged by a short-term feeding (6 h) of the unsaturated fatty acids (24), it remained unclear whether the decline of jejunal
CRBP II mRNA in response to the dietary fat depletion for a long period
of time might be related to an alteration of PPAR-
mRNA expression.
In the second experiment, we explored whether PPAR-
mRNA level was
decreased by long-term feeding of a low-fat diet. Animals were fed an
isoenergic low-fat diet containing a minimal level (2.5%) of corn oil
to prevent essential fatty acid deficiency. As shown in Fig.
3, the abundance of jejunal PPAR-
mRNA
was significantly less (P < 0.01) in the rats fed the
low-fat diet than in the rats fed the control diet. The CRBP II mRNA
level in the rats fed the low-fat diet showed a three times lower level
than that in the rats fed the control diet.
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Effect of administration of 9-cis-RA concomitant with dietary fats in jejunal CRBP II gene expression. In experiments 3 and 4, we examined whether dietary retinol is required as a source of 9-cis-RA for eliciting the dietary fat-induced CRBP II gene accumulation. In experiment 3 rats prefed the vitamin A- and fat-free diet for 7 days were intubated into the stomach with MCT alone, 9-cis-RA with MCT, corn oil alone, or 9-cis-RA with corn oil. The amount of fat given to rats was 1.4 mmol/100 g body wt, which was assigned according to the daily intake of fat in rats fed the high-fat diet that was used in the previous study (7). The Northern blots of CRBP II mRNA extracted from the jejunum of the rats killed 6 h after the administrations are shown in Fig. 4A. The jejunal CRBP II mRNA level significantly increased in rats given corn oil alone, compared with those in rats given MCT alone (Fig. 4). The administration of 9-cis-RA with corn oil did not elicit additional accumulation of the mRNA. Also, the rats given 9-cis-RA with MCT exhibited no increase in CRBP II mRNA expression.
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DISCUSSION |
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We examined the effect of dietary fat depletion on jejunal CRBP II gene
expression in the first experiment. Compared with controls, rats
pair-fed the fat-free diet showed a remarkable reduction in
jejunal CRBP II mRNA expression as well as protein level during the
experimental period. This decrease in the mRNA level was very rapid,
reaching 50% of the level of day 0 within 1 day after
introduction of the fat-free diet despite the presence of an adequate
amount of vitamin A in the diet (Fig. 1). The present studies extend
our previous studies, which demonstrated that the CRBP II gene
expression was enhanced by dietary fat (7) or unsaturated fatty acids
(24). Thus the decrease in CRBP II mRNA expression in response to
depleting dietary fat may be related to some transcription-modulating
factor that may be activated by dietary fat. PPAR- is a candidate
for such a factor, because ligands for PPAR have been shown to include
a variety of long-chain unsaturated fatty acids (5, 14). Indeed the
data in experiment 2 showed that the rats fed a low-fat (2.5%
corn oil, wt/wt) diet for 7 days exhibited lower PPAR-
mRNA levels
than rats fed control (22.5% corn oil) diets (Fig. 3). The results
obtained from the first experiment further led us to hypothesize that
CRBP II gene expression might be dominated by the activation of
PPAR-
rather than the stimulation of retinoid signaling pathway,
because the animals consumed a diet containing the proper amount of
vitamin A throughout the experimental periods.
We found that the hepatic total retinol content in rats fed the fat-free diet was 14% lower than that of rats fed the 10% corn-oil diet. This result suggests the possibility that retinyl esters incorporated into chylomicron and exported to lymph were decreased due to the reduction of CRBP II protein level and the lack of fatty acid absorption. It has been poorly studied in intact animals whether the rate of retinol absorption would be correlated with the CRBP II protein level in small intestine. The study using Caco-2 cells overtransfected with CRBP II gene showed that CRBP II level would be a key determinant of retinol absorption (17, 18).
In the third experiment we examined whether the fatty acid-induced CRBP II mRNA accumulation would require dietary retinol as a source of 9-cis-RA in intestinal absorptive cells, which is a ligand for RXRs (8), using animals fed the retinol-depleted and fat-free diet for 7 days. The oral administration of long-chain triacylglycerols (LCT; corn oil) increased in a short period of time (6 h) CRBP II mRNA to a level twice that of rats given MCT, whereas the administration of 9-cis-RA with LCT did not bring about an additional increase (Fig. 4). These data suggested that dietary unsaturated fatty acids, but not retinoids, might be a critical determinant for the gene expression of CRBP II. However, because these animals were not completely vitamin A deficient, it should not be ruled out that they might have a minimal store of vitamin A in the intestine. Therefore, we explored whether orally administered corn oil could enhance CRBP II mRNA accumulation even in vitamin A-deficient rats in experiment 4.
Despite vitamin A deficiency, oral administration of corn oil alone
caused a significant elevation of jejunal CRBP II mRNA level within 6 h
(Fig. 5). However, the oral administration of 9-cis-RA with
corn oil did not elicit an additional increase in CRBP II mRNA
accumulation in the vitamin A-deficient rats (Fig. 5). As the serum
9-cis-RA was detected by the HPLC analysis in rats administered
9-cis-RA, we considered that the administered 9-cis-RA
was absorbed from the small intestine. The data obtained in the present
studies suggest that the CRBP II gene expression may not be dominated
by the retinoid signaling pathway, i.e., through RXR- activation,
because the CRBP II mRNA level in the jejunum of the vitamin
A-deficient rats did not respond to the 9-cis-RA
administration. These results suggest that dietary depletion of vitamin
A did not influence the fatty acid-mediated CRBP II mRNA induction.
Because it is technically extremely difficult to determine a trace
level of 9-cis-RA in intestinal mucosa, it still remains
unclear whether a very small amount of endogenous 9-cis-RA
store might have remained in the jejunum of vitamin A-deficient rats.
This would have been sufficient for activating the PPAR-
-RXR heterodimer.
Our previous studies (24) indicated that force-feeding diets containing
unsaturated fatty acids (linoleic, -linolenic, and oleic) increased
CRBP II mRNA level by 54-63% above the level in rats fed the
fat-free diet within 6 h, whereas a medium-chain fatty acid (caprylic)
and saturated fatty acids (stearic) elicited little effect on the CRBP
II mRNA level. Both RXR-
and PPAR-
, which are thought to interact
as a heterodimer with the cis element located in the CRBP II
gene promoter and to be activated by 9-cis-RA and long-chain
fatty acids and their metabolites, were constitutively expressed in the
rat jejunum, but the mRNA levels of these receptors were not increased
within 6 h by force-feeding of the unsaturated fatty acids (24). Thus
it is unlikely that the jejunal nuclear receptor levels of PPAR-
and
RXR-
should be changed in rats orally administered corn oil in
experiments 3 and 4, because of a short-term feeding
period. However, it was still an open question whether the PPAR-
level was influenced by long-term feeding of low-fat diet. The results
in experiment 2 indicate that long-term feeding (7 days) of a
low-fat diet brings about a decrease in PPAR-
mRNA level. These
results suggest that short-term feeding of unsaturated fatty acids may
increase ligands for PPAR-
and that a long-term feeding of
unsaturated fatty acids may increase PPAR-
mRNA levels as well as
the ligands for PPAR-
. Further study is required to explore these
speculations.
Recently, it has been suggested that RXRs may act as a
transcriptionally silent partner of other nuclear receptors,
exemplified by the signaling pathway of all-trans-RA, which is
known to be mediated through the heterodimer of RAR with a silent
RXR- (6, 21). This concept of silent RXRs may explain why the
9-cis-RA administration did not alter the CRBP II gene
expression in animals of the present study and why depletion or
administration of dietary fat brought about abrupt changes in the
expression levels of CRBP II transcripts. Thus the present study may
provide evidence supporting that RXR is a silent partner of PPAR-
in
vivo. It is likely that signaling through fatty acids would mediate the
CRBP II gene expression by a heterodimer of PPAR-
with a silent
RXR-
partner. Currently, not only some prostanoids (PGs
D2 and J2) but also a variety of long-chain
fatty acids are proposed to be putative ligands for PPARs (5, 14, 31).
In conclusion, our data indicate that the abrupt increase in CRBP II mRNA expression caused by dietary fat (corn oil) was independent of the vitamin A nutrition status and that dietary fatty acids may be physiologically key determinants for CRBP II gene expression in the small intestine.
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ACKNOWLEDGEMENTS |
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We are grateful to Nissin Oil (Yokohama, Japan) for generous supply of medium-chain triacylglycerols (MCT).
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FOOTNOTES |
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This work was supported by a Grant-in-Aid (01570088, 04670097) for Scientific Research from the Ministry of Education, Science, and Culture of Japan.
Address for reprint requests: S. Takase, Dept. of Nutrition, School of Food and Nutritional Sciences, Univ. of Shizuoka, 52-1 Yada, Shizuoka 422, Japan.
Received 4 November 1996; accepted in final form 19 December 1997.
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