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Institute for Nutrition Research,
*
Institute of Medical Biochemistry and
Laboratory of Molecular Embryology, University of Oslo, Norway;
**
Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892–4255; and
Department of Biochemistry, School of Medicine, Vanderbilt University, Nashville, TN
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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KEY WORDS: • vitamin A • cellular retinol-binding protein I • transgenic mice
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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). Retinoid toxicity is also reported in the
eye (Kamm 1982
). Furthermore, retinoids are important
for proper function of both male and female reproductive organs. One
effect of vitamin A deficiency or vitamin A excess is impaired
spermatogenesis, followed by reduced male fertility (Huang and
Marshall 1983
, Kurtz et al. 1984
, Unni et al. 1983
). Moreover, retinoids can influence growth and
differentiation of various hematopoietic cells (Blomhoff and Smeland 1994
). Abnormal intake of dietary vitamin A produces
hematopoetic disorders, with decreased levels of hemoglobin, hematocrit
and red blood cells (Donoghue et al. 1981
, Hodges et al. 1978
, Mejia et al. 1979
). It has also
been reported that retinoids are important for the immune system
(Blomhoff and Smeland 1994
).
In vitamin A–deficient rats, differentiated mature columnar epithelia
are replaced with squamous, keratinizing epithelial cells in several
tissues (De Luca et al. 1995
). Epithelia of the skin,
the trachea and the cervix can be considered as prototypes for most
other epithelia, which display the stratified, pseudostratified and
simple columnar phenotypes (Rosenthal et al. 1994
).
Under conditions of severe vitamin A deficiency, the endocervical
epithelium and the tracheal epithelium are gradually converted to a
stratified epidermoid-keratinizing phenotype resembling the
epidermis (Darwiche et al. 1993
, Lancillotti et al. 1992
). Moreover, excess vitamin A is associated with an
increased number of cell layers in the skin (Kamm et al. 1984
).
Retinoids are found in tissues bound to proteins. For retinol, two
intracellular binding proteins have been characterized: cellular
retinol-binding protein type I
[CRBP(I)]2
and cellular retinol-binding protein type II [CRBP(II)]
(Ong et al. 1994
). CRBP(I) is widely distributed in
several tissues. In contrast, CRBP(II) is highly restricted in
distribution; in the adult, only the small intestine contains CRBP(II).
The expression is restricted to the villus-associated enterocytes
that are active in absorbing vitamin A (Crow and Ong 1985
). In the intestine, CRBP(I) is present in the lamina
propria (Crow and Ong 1985
) and in the muscle layer
(Ong 1987
) but does not appear to play a direct role in
vitamin A absorption.
Recent data suggest that CRBP are important for proper metabolism of
retinol. Retinoic acid is an active metabolite that interacts with
nuclear receptors. Several in vitro studies using free retinol as
substrate have shown that alcohol dehydrogenase, as well as other
dehydrogenases, can oxidize retinol to retinoic acid (Kim et al. 1992
, Napoli and Race 1987
, Posch et al. 1989
, Siegenthaler et al. 1990
). However, recent
evidence indicates that the intracellular binding proteins protect
their ligands from nonspecific reactions with several enzymes, but
permit metabolism with other more specific enzymes. A microsomal
NADP-dependent retinol dehydrogenase has been identified that uses
retinol bound to CRBP(I) as substrate (Posch et al. 1991
). Further metabolism to retinoic acid occurs with a
cytosolic NAD-dependent dehydrogenase that utilizes CRBP-bound
retinaldehyde as substrate (Ottonello et al. 1993
,
Posch et al. 1992
). These studies showed that apoCRBP(I)
is a specific inhibitor of retinoic acid synthesis from retinol bound
to CRBP(I). It has therefore been hypothesized that activation of
retinol to retinoic acid is controlled in part by the relative amounts
of apoCRBP(I) and holoCRBP(I) (Napoli et al. 1991
).
Retinol bound to CRBP(I) may also be esterified with long-chain
fatty acids by the enzyme lecithin:retinol acyltransferase (LRAT)
(Herr and Ong 1992
, Ong et al. 1988
,
Yost et al. 1988
).
Recently, we developed transgenic mice expressing high levels of human
CRBP(I) [hCRBP(I)] in several tissues (Trøen et al. 1996
). The concentrations of retinyl esters in liver, lung and
kidney did not differ, however, between transgenic and control mice,
and the concentration of total retinol in plasma was within the normal
range in transgenic mice. Furthermore, feeding transgenic mice a diet
with high or low concentrations of vitamin A for 2 wk resulted in no
marked differences in the concentrations of retinyl esters in various
organs compared with control mice. Thus, our previous study indicated
that the CRBP(I) content alone does not control retinyl ester storage
in vivo.
In this report, we have tested in vivo whether the metabolism of retinol is controlled by the level of CRBP(I). More specifically, our aim was to examine whether high expression of hCRBP(I) induced a phenotype resembling vitamin A toxicity as a result of an increased production of retinoic acid, or whether hCRBP(I) induced a vitamin A–deficient phenotype as a result of an increased accumulation of vitamin A in storage cells.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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The production and initial characterization of the hCRBP(I) transgenic
mice have been described elsewhere (Trøen et al. 1996
).
Briefly, a fusion plasmid was constructed in which the mouse
metallothionein (mMT) promoter region
(EcoRI-BamHI fragment of the mouse
metallothionein-human growth hormone fusion plasmid,
MThGH111, Palmiter et al. 1983)
was fused to the human
CRBP(I) cDNA (provided by Dr. Ulf Eriksson, Ludwig Institute for Cancer
Research, Stockholm, Sweden, Colantuoni et al. 1985)
.
Linearized DNA was microinjected into mouse embryos; transgenic mice
were identified by polymerase chain reaction analysis of tail DNA, and
mice were bred according to established procedures.
Diets.
Mice consumed food and water ad libitum, and body weights were recorded routinely. Mice were fed a normal diet (EWAR Sverige AB, Sweden) containing 4.3 mg retinyl acetate/kg. A vitamin A–enriched diet (Special Diets Services, Witham, Essex, UK) containing 40 mg retinyl acetate/kg and a vitamin A–deficient diet (Special Diets Services) containing 0.20 mg retinyl acetate/kg were given to groups of mice for 2 wk before killing. Except for vitamin A, the diet compositions were similar (~5 g fat, 55 g carbohydrate and 17 g protein per 100 g diet). To induce expression of the mMT-hCRBP(I), 75 mmol/L ZnSO4 was supplied in drinking water for 2 wk before mice were killed.
In most experiments, the mice were analyzed at 8 wk of age after anesthesia with Dormicum/Hypnorm (1:1). Mice were treated in accordance with the ethics rules of the Norwegian government.
Preparation of tissue extract and immunoblot analysis.
Tissues were homogenized with a Dounce homogenizer in 5 vol buffer
(wt/v) [0.01 mol/L sodium phosphate, pH 7.5, containing 0.14 mol/L
NaCl, aprotinin (24 x 103 TIU/L),
phenylmethylsulfonyl fluoride (0.5 mmol/L) and leupeptin (1
mmol/L)], sonicated 2 x 15 s at 50% efficiency and
centrifuged at 20,000 x g for 30 min. Protein
concentrations were determined by the dye-binding assay of
Bradford (1976)
, according to the protocol from
Bio-Rad Laboratories (Munich, Germany). Retinoids in tissues were
analyzed as described previously (Gundersen et al. 1997
,
Gundersen and Blomhoff 1999
).
Proteins from tissue extracts were fractionated on 14% acrylamide gels
(Tris-Glysine PAGE gels, San Diego, CA), electroblotted into
polyvinyldifluoride membranes (LC 2002, NOVEX, San Diego, CA) and
probed with a polyclonal rabbit anti-hCRBP(I) antiserum (1:1000) as
described (Trøen et al. 1996
).
Retinol-binding assay.
Tissue extracts were incubated with 0.16 mmol/L
[11,12-3H]-retinol (NET 927, 1.6 TBq/mmol DuPont
de Nemours GmbH, NEN Division, Dreiech, Germany) in the absence (total
binding) and presence (nonspecific binding) of 500-fold excess
unlabeled retinol for 3 h. The level of specific
[3H]retinol binding to hCRBP(I) was measured after
protein fractionation as described elsewhere (Nilsson et al. 1997
). Specific binding is defined as the difference between
total and nonspecific binding.
Isolation of cells from testis.
Cells were isolated from testes of mice essentially as described by
Eskild et al. (1991)
. Testes from eight transgenic and
nine control 17- to 19-d-old mice were used. For the isolation of cells
from 56-d-old mice, we used four control mice and three transgenic
mice.
Preparation of tissue sections from intestine.
Small intestine was washed with PBS, pH 7.4, and tissue sections were
fixed in PerFix solution (1.3 mol/L paraformaldehyde, 0.12 mol/L
trichloracetic acid, 0.15 mol/L zinc chloride, 20% isopropyl alcohol)
for 2–3 h, dehydrated in 70% ethanol and embedded in paraffin.
CRBP(I) was localized in sections (5 µm) by using the
ABC method described by Crow and Ong (1985)
. The
reagents were purchased from Vector Laboratories (Burlingame, CA).
Briefly, the tissue sections were deparaffinized in xylene, incubated
for 30 min in 0.3% H2O2 in 100% methanol to
inactivate endogenous peroxidases and rehydrated. The sections were
then incubated for 20 min at 37°C in 1.8% normal goat serum/2.5%
bovine serum albumin/0.1 g/L Triton X-100/9 g/L NaCl/0.05 mol/L Tris
chloride, pH 4.4. Affinity-purified anti-human CRBP(I) was applied
to the tissue sections for 1 h at 37°C followed by incubation
with ABC for 60 min. Diaminobenzidine and H2O2
were used as substrates for the peroxidase to produce the brown stain
that reveals the presence of immunoreactive substances in the sections.
The sections were counterstained with hematoxylin.
Preparation of intestinal mucosa and muscle layer.
The small intestine was removed and treated essentially as described by
Herr et al. (1993)
. First, the small intestine was
flushed with PBS, pH 7.4, and cut longitudinally to expose the mucosal
layer. The opened intestine, muscle side down, was then placed on a
glass plate resting on ice and divided into two segments of equal
length. The mucosa from the upper half of the small intestine was
scraped free using the edge of a glass microscope slide. The remaining
muscle layer was rinsed with PBS, and tissue extracts from the two
intestinal layers were prepared as described earlier.
Histochemical analysis in testis and eye.
Tissues were fixed in formalin, embedded in paraffin blocks, sectioned at 5 µm, stained with hematoxylin/eosine and morphology analyzed by light microscopy.
Hematology.
Blood was collected from the vena cava inferior into tubes containing 10 µL of 0.5 mol/L EDTA, pH 7.4, and plasma was harvested by low-speed centrifugation. Hematology analysis was done using a Technicon hematology apparatus H*1 (Technicon, Territown, NY). Cells were counted automatically and different hematologic variables were measured.
Immunohistochemical analysis of skin, trachea and cervix.
Tissue was washed with PBS, pH 7.4, quickly fixed in 70% ethanol, and
paraffin-embedded sections (5 µm) were prepared
for immunohistochemical staining as described (Darwiche et al. 1993
). Briefly, the sections were exposed to
affinity-purified rabbit antiserum, specific for keratin K5, for
2 h at room temperature. The sections were then exposed to
biotinylated goat anti-rabbit secondary antibodies and the
vectastatin ABC kit was used (Vector Laboratories). Peroxidase staining
was performed using Histomark Streptavidin-HRP Systems obtained
from Kirkegaard and Perry Laboratories (Gaithersburg, MD). The sections
were also stained with contrast Green.
Statistical analysis.
The values for different hematologic variables are given as means
± SD. Comparison of difference between transgenic and
nontransgenic mice was evaluated by Student's t test
(two-tailed). Differences with P-values 
0.05
were considered significant.
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS AND DISCUSSIONREFERENCES |
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In a previous study with MT-hCRBP(I) transgenic mice, we demonstrated
that the MT promoter was able to promote the expression of hCRBP(I) in
several tissues as shown by Northern and immunoblot analysis
(Trøen et al. 1996
). The expression was particularly
high in intestine and testes. The total level of CRBP(I) [i.e., the
endogenous mouse CRBP(I) and the transgene hCRBP(I)] was 6–15 times
greater in testes from transgenic mice compared with control mice. In
intestine, CRBP(I) was not detected in control mice. However, the
tissues of transgenic mice showed a stong CRBP(I) band. Figure 1
Ashows typical immmunoblots obtained with testes and intestine from
MT-hCRBP(I) transgenic mice.
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Sertoli cells normally contain CRBP(I) and LRAT (Schmitt and Ong 1993
) and are able to synthesize and release
retinol-binding protein for delivery of retinol to germ cells
(Davis and Ong 1992
). Recently, peritubular cells have
also been shown to contain CRBP(I), suggesting that they are involved
in processing retinol to the tubules (Davis and Ong 1995
). CRBP(I) is not detected in germ cells (Eskild et al. 1991
), but Schmitt and Ong (1993)
showed
that they contain LRAT activity. These results indicate that the germ
cells receive retinol from Sertoli cells and are able to synthesize
retinyl esters themselves.
The cell-specific expression of hCRBP(I) in testes was studied in
enriched cell fractions containing mainly seminiferous tubules (Sertoli
cells and germ cells) and peritubular cells (myofibroblasts). First, to
study whether germ cells are responsible for the increased CRBP(I)
expression in testes, we isolated seminiferous tubules and peritubular
cell fractions from 17- to 19-d-old mice. Because the production of
germ cells is initiated around this age in mice, this seminiferous
tubule fraction is enriched in Sertoli cells. As demonstrated in Figure 1
B(a), the level of immunoreactive CRBP(I) was not
elevated in either cell fraction in transgenic mice.
We also examined the expression of hCRBP(I) in seminiferous tubules and
peritubular cell fractions from 8-wk-old mice because the seminiferous
tubules of such mice contain fully developed germ cells in addition to
Sertoli cells. As shown in Figure 1
B(b), both the
seminiferous tubule fraction and the peritubular cell fraction isolated
from 8-wk-old transgenic mice expressed a higher level of
immunoreactive CRBP(I) than those of control mice.
These data demonstrate an age-dependent increase in the expression of the transgene in myofibroblasts in the peritubular cell fraction. The data also show an age-dependent increase in hCRBP(I) in the seminiferous tubule fraction. This may be due either to expression of hCRBP(I) in the germ cells or to an increase in hCRBP(I) expression in Sertoli cells with age. Thus, hCRBP(I) is expressed in transgenic adult mice in the peritubular myofibroblasts and in one or both of the seminiferous tubule cell types.
The expressed transgene, hCRBP(I), is a functional retinol-binding protein.
To confirm that the hCRBP(I) protein retained the expected retinol-binding capacity in transgenic mice, we examined the specific binding of retinol to extracts from the isolated seminiferous tubule fractions. Specific [3H]retinol binding to CRBP(I) was demonstrated in this fraction isolated from transgenic mice. The retinol-binding capacity of CRBP(I) was 1.98 MBq/mg protein (1.50–2.22; mean and range of triplicate determinations) in transgenic mice and 0.26 MBq/mg protein (0.17–0.44; mean and range of triplicate determinations) in control mice. Thus, the seminiferous tubule fractions from transgenic mice have ~7 times higher specific binding of retinol to CRBP(I) compared with the same fraction from control mice, indicating that hCRBP(I) expressed in transgenic mice retained its retinol-binding capacity.
Normal metabolism of [3H]retinol in hCRBP(I) transgenic mice.
Six hCRBP(I) transgenic mice and six control mice were given orally 1.2 MBq [11,12-3H]retinol (1.85 TBq/mmol) in 100 µL peanut oil. Mice were killed after 6 h and tissues were immediately frozen at -80°C. Radioactive retinol, retinyl esters and all-trans retinoic acid were determined in liver and testis. No differences were observed between the groups (data not shown). There was no difference in mass concentration of all-trans retinoic acid or all-trans retinol in testis. The levels of all-trans retinol in testis from normal and transgenic mice were 584 ± 171 and 594 ± 311 pmol/g (mean ± SD, n = 6), respectively. The corresponding values for all-trans retinoic acid were 43 ± 20 and 33 ± 23 pmol/g (mean ± SD, n = 6), respectively.
No abnormalities in gross morphology in testes of hCRBP(I) transgenic mice.
Testis is a vitamin A–sensitive tissue, demonstrating high functional
and morphological abnormalities in both vitamin A excess and
deficiency. Both instances can lead to impaired spermatogenesis,
massive morphological degeneration of seminiferous epithelium and
reduction of tubule volume (Huang and Marshall 1983
,
Kurtz et al. 1984
, Unni et al. 1983
).
Microscopy of sections of testis from hCRBP(I) transgenic mice
revealed, however, that the seminiferous epithelium had normal
thickness. We did not observe any shrinkage or degeneration of
seminiferous tubules. Representative histologic sections are shown in
Figure 2
A and
B(transgenic mice) and Figure 2
C (control mouse). Treatment
of mice for 2 wk with a vitamin A–enriched or a vitamin A–deficient
diet did not cause the development of differences between nontransgenic
and transgenic mice (data not shown). Thus, although testes from
transgenic mice express ~10 times more CRBP(I) and ~6 times higher
CRBP(I) retinol-binding capacity compared with control mice, no
abnormal histology was found. These data suggest that overexpression of
hCRBP(I) in testes does not result in increased retinoic acid
production as would have been revealed by a vitamin A–toxic phenotype.
Nor was a vitamin A–deficient phenotype observed as could have been
envisioned as resulting from an increased accumulation of retinol by
apoCRBP(I) or from lowered local retinoic acid concentrations due to
redirection of retinol to LRAT esterification and storage. The normal
morphology revealed in testes, at least within the time frame of this
study, is in agreement with the fact that the mice are fertile.
|
Intestine from transgenic mice showed a strong CRBP(I) band on
immunoblot analysis (Fig. 1
A). By using immunohistochemical
staining of sections from intestine, we observed more staining of
CRBP(I) in smooth muscle, localized particularly in the outer layer, in
transgenic mice compared with control mice (Fig. 3
). Because the antibody against hCRBP(I) used in the
immunohistochemistry cross-reacts with the endogenous mouse
CRBP(II), which is specifically localized in enterocytes, it is not
possible from these experiments to assess differences in enterocytes.
|
, an intense reaction of immunoreactive CRBP(I) was found in transgenic
mice in the mucosal fraction compared with control mice. The immunoblot
also confirmed that the smooth muscle cells in transgenic mice
contained somewhat higher amounts of CRBP(I) than did controls. These
data suggest that the large increase in intestinal CRBP(I) in
transgenic mice is due mainly to a high level of expression of hCRBP(I)
in enterocytes and to some degree to expression of the transgene in
smooth muscle cells in the outer layer.
|
The gross morphology of the small intestine has been reported to be
affected only moderately by vitamin A deficiency, whereas no
morphologic changes have been observed as a result of vitamin A
toxicity. In vitamin A deficiency, a reduction in number of goblet
cells along the intestinal villus has been found in a series of reports
(De Luca and Wolf 1972
, Olson et al. 1981
, Rojanapo et al. 1980
). In vitamin
A–depleted lambs, the apical epithelium was separated from the
underlying lamina propria (Holland et al. 1993
).
As shown in Figure 3
A and B, the hCRBP(I)
transgenic mice had a normal intestinal gross morphology. Furthermore,
no difference in the number of goblet cells was observed. Thus, a high
expression of hCRBP(I) in enterocytes and a moderate expression in
smooth muscle cells did not alter the structure of the cells of the
small intestine.
Lack of signs of vitamin A toxicity or deficiency in other tissues.
Although no abnormalities in vitamin A metabolism have been detected in
hCRBP(I) transgenic mice (Trøen et al. 1996
), a
systemic effect of increased CRBP(I) expression may have occurred,
resulting from either a change in the flux of vitamin A or an influence
on the levels of various active retinoids in plasma or tissues.
Evidence for such a systemic effect was tested in the eye, a tissue
that is very sensitive to vitamin A status and in which signs of both
vitamin A deficiency and toxicity can be demonstrated (Berson 1982
, Kamm 1982
). Microscopical analysis of
sections from eye, however, showed normal gross morphology in
transgenic mice fed the normal diet and the two diets with high or low
levels of vitamin A. We especially looked for cell degeneration or
abnormalities in the cornea (Fig. 5
A and
B) and changes in the outer segments of the retina (Fig. 5
C and
D), but no signs of abnormalities were detected in eyes of
transgenic mice.
|
A and
B). Similar results were found in control mice (data not shown). Two
weeks of consuming a vitamin A–deficient diet did not cause squamous
metaplasia in transgenic mice (data not shown). Thus, no effects of the
transgene were observed on the gross morphology as well as the K5
staining of the epithelium of the reproductive organs of female mice.
Immunohistochemistry with sections from tracheas and skin did not show
any abnormalities in transgenic mice (data not shown).
|
, Hodges et al. 1978
, Mejia et al. 1979
). However, we found no
significant differences between transgenic and control mice when
comparing levels and distribution of different hematopoietic variables.
The hemoglobin concentrations, hematocrits and the number of red blood
cells were within normal ranges in the transgenic mice fed the normal
diet or the two diets with high or low levels of vitamin A (Table 1).
|
). Thus, these data suggest that
overexpression of CRBP(I) does not influence retinol metabolism and
function. An alternative explanation, however, may be that a modest
change in retinoid metabolism has occurred, but that the effects may
not have been established during the time course of this study.
Moreover, we cannot exclude the possibility that compensatory retinoid
metabolism may have hidden any effect of the ectopic CRBP(I)
expression.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Abbreviations used: CRBP(I), cellular
retinol-binding protein type I; CRBP(II), CRBP type II; hCRBP(I),
human CRBP(I); LRAT, lecithin:retinol acyl-transferase; MT,
metallothionein; mMT, mouse MT.
Manuscript received January 19, 1999. Initial review completed February 16, 1999. Revision accepted May 28, 1999.
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