Department of Medicine, Denver Veterans Affairs Hospital, University of Colorado Health Sciences Center, Denver, Colorado 80262
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ABSTRACT |
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Hepatic alcohol dehydrogenase (ADH) activity is higher in female than in male rats. Although sex steroids, thyroid, and growth hormone (GH) have been shown to regulate hepatic ADH, the mechanism(s) for sexual dimorphic expression is unclear. We tested the possibility that the GH secretory pattern determined differential expression of ADH. Gonadectomized and hypophysectomized male and female rats were examined. Hepatic ADH activity was 2.1-fold greater in females. Because protein and mRNA content were also 1.7- and 2.4-fold greater, results indicated that activity differences were due to pretranslational mechanisms. Estradiol increased ADH selectively in males, and testosterone selectively decreased activity and mRNA levels in females. Effect of sex steroids on ADH was lost after hypophysectomy; infusion of GH in males increased ADH to basal female levels, supporting a role of the pituitary-liver axis. However, GH and L-thyroxine (T4) replacements alone in hypophysectomized rats did not restore dimorphic differences for either ADH activity or mRNA levels. On the other hand, T4 in combination with intermittent administration of GH reduced ADH activity and mRNA to basal male values, whereas T4 plus GH infusion replicated female levels. These results indicate that the intermittent male pattern of GH secretion combined with T4 is the principal determinant of low ADH activity in male liver.
growth hormone; thyroxine; hypophysectomy; estrogen; testosterone
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INTRODUCTION |
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LIVER IS THE MAJOR SITE of ethanol clearance and its subsequent metabolism (8). Ethanol is oxidized principally by two major pathways primarily involving alcohol dehydrogenase (ADH) and CYP2E1 (11, 30). These enzymes are located in the cytosol and endoplasmic reticulum, respectively, and oxidize ethanol to acetaldehyde, which is rapidly metabolized to acetate by aldehyde dehydrogenase (ALDH) (8). ADH is rate limiting in ethanol oxidation and is believed, under normal circumstances, to metabolize the majority of ethanol. Although ADH consists of at least five different classes, class I is the predominate form in rat liver (16). ADH is principally expressed in liver and is hormonally, nutritionally, and developmentally controlled (2, 36, 42).
Although the mechanism(s) is unclear, ADH is dimorphically expressed, with higher specific activity values in female compared with male rats (4, 51). Some authors have shown that estrogen increased and testosterone decreased hepatic ADH activities, whereas others have found no effect (40, 41, 52). Growth hormone (GH) has also been shown to be important in regulation of hepatic ADH-specific activity and transcriptional regulation of mRNA in vivo and in vitro, respectively (39, 49). Sexual dimorphic expression of hepatic genes in rats is most often due to sexual difference in the GH secretory pattern, which is regulated, in part, by sex steroid hormones (20, 54). Therefore, it is unclear whether exogenous sex steroid hormones alter expression of ADH directly or indirectly through changes in GH secretion. Additionally, thyroidectomy increased hepatic ADH in both sexes, which may be a direct effect or possibly secondary to modulation of serum GH levels (14). In contrast, adrenalectomy had no effect in male rats (39).
Previous studies, for the most part, have not directly addressed the possible role of the GH secretory pattern in mediating the effect of sex steroid hormones on expression of hepatic ADH. Therefore, the present studies were undertaken in gonadectomized and hypophysectomized (Hx) male and female rats to examine the molecular mechanisms involved in the sexual dimorphic expression of hepatic ADH.
The results indicate that the pattern of GH secretion in concert with thyroid hormone is principally responsible for regulation of hepatic ADH mRNA and protein levels. A novel observation was that the dimorphic expression of ADH is due to the downregulation of constitutive ADH expression.
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MATERIALS AND METHODS |
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Animals.
Adult male and female Sprague-Dawley rats (weighing 185-200 g)
were purchased from Harlan (Indianapolis, IN). The supplier performed
all surgeries. Animals were allowed to stabilize for a minimum of 6 days within our facility before treatment. If Hx rats gained weight,
they were eliminated from the study. Food and water were allowed ad
libitum until 18 h before death, when food was removed. Animals
were killed by 9 AM. All animals were exposed to 12:12-h of light-dark.
All agents except for bovine GH (bGH) were purchased from Sigma and
were the highest purity available. bGH was kindly supplied by Protiva
(Monsanto) and the USDA-Animal Research Science research
hormone programs. bGH was administered continuously at 60 µg · 100 g1 · day
1 for 7 days or intermittently at twice-daily 30 µg/100 g sc for 7 days. The
solvent for bGH was 0.05 M Na2PO4, pH 8.8, 1.6% glycerol, and 0.02% NaN2. For all continuous
infusions, Osmotic minipumps (model 2001; Alzet) were placed
subcutaneously for the length of time indicated in the figures.
L-Thyroxine, sodium salt (T4) was dissolved in
normal saline and administered once daily at 50 µg · kg
1 · day
1 ip for 7 days. 17
-Estradiol (
-E) and testosterone enanthate (TE) were
dissolved in corn oil, and injections were administered at 100 and 2 µg · kg
1 · day
1 sc,
respectively, for 14 days as indicated in the figures and tables.
Enzyme activities.
Under ether anesthesia, livers were rapidly removed, and homogenates
were prepared as follows: 0.25 g of minced liver was added to 3.0 ml of isolation buffer [15 mM Tris · HCl, 300 mM mannitol, 5 mM EGTA, protease inhibitor tablets (Boehringer Mannheim)]. This
sample was Dounce homogenized and ultracentrifuged at 150,000 g for 40 min to prepare cytosolic fractions and was stored
at 80°C. Mitochondrial fractions were isolated in mannitol buffers as previously described (55). All procedures were
conducted at 4°C. ADH-specific activities were determined
spectrophotometrically using 25 mM ethanol as substrate at pH 10.0 and
37°C according to the modified method of Algar et al.
(1). ALDH was also measured spectrophotometrically in
cytosolic and mitochondrial fractions using the method of Little and
Peterson (31) using 50 µM and 5 mM propionaldehyde as
substrate, respectively, and 1.2 mM NAD as cofactor at pH 7.4 and 32°C. Protein was measured according to Lowry et al.
(32). Specific activities of both enzymes are expressed as
nmol · mg protein
1 · min
1.
Immunoblots of ADH. Content of ADH protein was measured in liver cytosol fractions using PBS, pH 7.5, containing protease and phosphatase inhibitors. Protein content of ADH was determined by immunobloting using a monospecific anti-class I ADH antibody (provided by William Bosron, University of Indiana Medical School). SDS-PAGE and immunobloting were carried out using minigels for enhanced chemiluminescence (ECL). After electrophoresis, cytosolic proteins were transferred to Hybond ECL membranes (Amersham) by the procedure of Towbin et al. (59) at 167 V for 1 h using a high transfer apparatus by Ideal. Gels were blocked for 1 h using 5% Tween/TBS and processed for ECL detection (Amersham) using 1% milk in TBS for antibody diluent. Blots were visualized by streptauidin horseradish peroxidase detection system (Amersham). Washes were with 0.5% Tween/TBS for 5 min (3×). ECL blots were placed in plastic film and exposed to Amersham Hyperfilm for ECL for 30-60 s. Autoradiograms were quantitated by densitometry using a Bio-Rad laser imaging densitometry.
Preparation and analysis of RNA.
Total RNA was extracted from whole liver using RNeasy Mini Kit
(Qiagen). The RNA was fractionated in 1.2% agarose-formaldehyde gels
in borate buffer at 140 V for 4 h. RNA was transferred to Hybond
N+ (Amersham) with high-efficiency transfer solution
(Tel-Test) by capillary action and fixed by ultraviolet crosslinking.
cDNA probes were labeled with [32P]dCTP (Amersham) using
Decaprime II (Ambion) random-primed labeling system. Unincorporated
label was removed with Probequant G-50 microcolumns (Pharmacia).
Membranes were hybridized using a high-efficiency hybridization system
(Tel-Test) for 16 h at 62°C and washed twice in 2× SSC/0.1%
SDS followed by two washes in 0.1× SSC/0.1% SDS, all at 55°C for 20 min. Membranes were exposed to Hyperfilm MP with intensifying screen at
70°C for 3 h. Autoradiograms were quantitated with an imaging
densitometer. The following probes were used: ADH (provided by Vincent
Yang, Johns Hopkins Medical School), ALDH2 (provided by Henry Weiner,
Purdue University), CYP2C11 and CYP2C12 (provided by Agneta Mode,
Karolinska Institute), and 5
-reductase (provided by David Russell,
University of Texas Southwestern, Dallas). The relative density of mRNA
was normalized to 18S rRNA (Ambion) and expressed as a percentage of
the male control.
Data analysis. Data were expressed a means ± SE and analyzed statistically by using two-way ANOVA, followed by post hoc analysis with Tukey's test. Other comparisons among groups were made using the Student's t-test. A P value of <0.05 was determined to be statistically significant.
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RESULTS |
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Analysis of sexual differences in ADH and ALDH.
ADH-specific activities were measured in liver homogenates and cytosol
fractions from male and female rats. Although values are higher in
cytosol, similar sexual differences in ADH-specific activities were
obtained in liver homogenate as well as cytosol (Fig.
1A). ADH-specific activities
in homogenate and cytosol fractions were 2.1- and 1.8-fold
(P < 0.001) higher in females compared with males,
respectively. To confirm that differential expression of ADH was due to
protein content, liver cytosol fractions were isolated and, after
separation by SDS-PAGE, were immunoblotted with a monospecific antibody
against rat ADH. ADH peptides were recognized as single 40-kDa bands as
shown in Fig. 1B. Female rats showed a significantly
(P < 0.01) increased ADH protein content compared with
males (68%). Because the density of ADH protein and enzyme activity
was similar, the dimorphic expression of ADH was due to
pretranslational mechanisms.
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Changes in weight gain in male and female rats with hormonal
status.
Because it is known that fasting and food restriction
posttranslationally decrease hepatic ADH activity (3, 27,
33), we measured changes in weight gain with different hormonal
manipulations. Patterns of weight gain/loss are shown for male and
female rats in Table 1. As other studies
(15) have shown, female rats gain significantly less
weight than their male littermates. Thus the effect of -E,
castration, Hx, and TE were compared with gender-matched controls.
-E significantly (P < 0.05) decreased weight gain
in both male and female rats, whereas castration and TE had no effect. On the other hand, Hx stopped weight gain in both sexes, as previously shown (47). Administration of GH either by injection or
infusion increased weight gain, and as previously shown, the male
pattern of GH administration is more effective that the female infusion pattern (6, 47). In contrast,
-E in males and
T4 in females decreased weight gain in Hx animals. Weight
loss associated with estradiol administration was probably related to
its known effects on food aversion (18).
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Effect of castration and sex steroid hormones on ADH-specific
activity and mRNA levels.
Although some studies have shown that estrogens increased and
testosterone decreased hepatic ADH-specific activity, other studies
(41, 42, 50, 52, 58) failed to confirm these results.
These studies used short time courses of hormone treatments, and most
did not examine whether sex steroids altered ADH mRNA levels.
Therefore, we examined the effect of testosterone and estrogen given
intermittently for 14 days to intact and castrated (Cx) male and female
rats to determine whether changes in ADH-specific activity were related
to pretranslational processes. The results are shown in Table
2 and Fig.
2, A and B. As
shown in Table 2, castration in male rats significantly
(P < 0.05) increased ADH activity, whereas TE
administration restored values to control levels. -E administration
to intact males also significantly (P < 0.01)
increased ADH-specific activity; whereas in female rats, ovariectomy
(Ovx) and testosterone significantly reduced ADH-specific activity. In
contrast to its effects in males,
-E had no effect in female rats.
Furthermore, testosterone given to intact females, but not males,
reduced activity (data not shown). These results indicated that
testosterone and estrogen selectively altered ADH-specific activity,
possibly accounting for the difference in reported results.
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Effect of GH secretory patterns on ADH-specific activities and mRNA
levels.
Two experiments were designed to test the possibility that GH secretion
modifies ADH. First, if estrogen and testosterone effects on ADH were
mediated through pituitary hormones, we anticipated that Hx would
prevent changes in ADH induced by sex steroid hormone administration.
The results of Hx and its effect on estrogen and testosterone
alteration of ADH activity and mRNA are shown in Table
3 and Fig.
3A. In male rats,
ADH-specific activity was increased approximately twofold by Hx to
values greater than those measured in intact females (Table 3), whereas
values in females were also significantly increased by 46%
(P < 0.01). However, the administration of
-estradiol paradoxically decreased ADH-specific activity in both
sexes. On the other hand, ADH activity was unchanged with TE
administration.
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Pretranslational regulation of hepatic ADH by pituitary hormones in
Hx rats.
Previous studies have shown complex hormonal regulation of ADH by
pituitary hormones, but the mechanisms and interactions of these
hormones in determination of the sexually dimorphic expression of ADH
are unclear (9, 10, 42). Therefore, we examined whether
the mode of GH administration was of primary importance in the
regulation of the dimorphic expression of hepatic ADH activity. Table
4 demonstrates the effect of Hx and
different GH replacement patterns in male and female rats on hepatic
ADH-specific activities. Hx significantly (P < 0.05)
increased ADH-specific activity in male and female rats 2.5- and
1.4-fold, respectively. Intermittent administration of GH after Hx in
male and female animals only modestly (<0.05) decreased ADH activity,
whereas infusion of GH did not significantly change values. Thus loss
of pituitary hormones selectively increased ADH activity especially in
males, whereas GH administration alone did not restore ADH levels in
either sex to basal male values.
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DISCUSSION |
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Hormonal regulation of ADH has been extensively examined by a number of laboratories using in vivo animal models, hepatocytes, and cultured liver cell lines (8, 36). However, previous studies did not establish whether sex steroid hormones or GH were primarily responsible for the sexual dimorphic expression of ADH. Furthermore, the molecular mechanism(s) involved in increased ADH-specific activity in female rat liver has not been examined. In the present study we used Hx and gonadectomized as well as intact male and female rats given hormones to establish that the primary mechanism for differential sexual expression of ADH is mediated by pretranslational processes through the intermittent secretion of GH in combination with T4.
A number of hepatic proteins are under complex regulatory controls by hormones that determine their sex-specific expression (19, 28). Sexual dimorphic gene expression in liver can be controlled by three distinct but overlapping mechanisms: 1) androgen imprinting during a critical period in development, 2) circulating gonadal hormones in the adult, and 3) pattern of GH secretion. The secretory pattern of GH is perhaps the most common mechanism involved in the sex-specific expression of hepatic genes, especially those involved in drug metabolism. Pituitary GH secretion is pulsatile, with the frequency of pulsations being sex-dependent and under the influence of gonadal hormones (24). In adult female rats, a high pulse frequency results in the continuous presence of GH in the circulation at levels in excess of 10-20 ng/ml of plasma. By contrast, in adult male rats GH is present in plasma intermittently, with regular peaks detected every 3-4 h followed by trough periods of no detectable GH (15). These sexually differentiated plasma GH profiles in turn regulate expression of a number of liver-specific hepatic genes (12). Female-specific CYP2C12 is positively regulated by the continuous plasma GH pattern, whereas expression of male-specific CYP2C11 is stimulated by the male pattern of intermittent GH pulsations (56). However, expression of some male-specific genes is primarily derived from the suppressive influences of the continuous pattern of plasma GH rather than the positive influence of the male intermittent pattern (5, 13, 35, 45). GH pretranslationally and directly regulates these hepatic sex-dependent cytochrome P-450 enzymes (21, 29).
Changes in body weight were measured to determine adequacy of hormonal
ablation and replacement protocols. In addition, it is known that
starvation and caloric restriction decreases ADH levels primarily by
posttranslational mechanisms (3, 33). As other studies
(24) have shown, untreated males gain weight faster than
females. Importantly -E but not testosterone treatment markedly
reduced weight gain in both intact male and female animals (60). Hypophysectomy, as expected, prevented weight gain
that was restored with GH replacement, indicating adequacy of pituitary ablation and hormone replacement. In contrast, sex steroid hormones and
T4 administration to Hx rats did not restore weight gain; and importantly
-E especially in Hx males and T4 in Hx
females significantly reduced weights. These later changes may
contribute, in part, to reduced ADH activity and mRNA levels.
Studies have shown that hepatic ADH-specific activity is higher in female rats compared with males (4, 9, 51, 52), but the mechanism(s) is unclear. Androgens downregulated ADH-specific activity in some studies (37, 40, 43), but not others (9, 10), whereas estrogens increased hepatic ADH-specific activity in male rats but not females (41, 57, 58). Furthermore, it is unclear whether sex steroid hormones alter ADH activity directly in the liver or rather through modulation of the GH secretory pattern (9). Previous studies, in addition, did not examine the molecular mechanisms involved in the sexual dimorphic expression of hepatic ADH. The purpose of the present study was, therefore, to fill in these gaps and to determine the physiological and molecular mechanisms involved in the sexual dimorphic expression of ADH.
Consistent with previous reports, hepatic ADH-specific activity was approximately twofold greater in both liver homogenates and cytosols from female rats compared with males (4, 52). In addition, we demonstrated that ADH protein content and steady-state mRNA levels were 1.8- and 2.4-fold greater in females, respectively, thus indicating that the sexual dimorphic expression of hepatic ADH is pretranslationally regulated. To examine whether sex steroid hormones were responsible for the dimorphic expression of hepatic ADH, male and female rats were either castrated or given hormones. Estrogens increased ADH-specific activity and mRNA levels in males, whereas androgens decreased ADH levels in females, consistent with sex-specific changes in ADH. However, neither administration of estrogens in males nor testosterone in females completely restored the dimorphic expression. This partial response may be due to hormonal imprinting established in the neonatal period (25, 26).
Selective gender effects of estrogens and androgens on ADH suggested
that the differential effect might be mediated secondary to alterations
in the GH secretory pattern rather than a direct effect on the liver.
This proposal was supported by the following observations:
1) -E administration to Hx rats did not increase ADH
activity or mRNA in either sex; 2) testosterone
administration had no effect on ADH in Hx rats of either sex;
3) changes in the female-dominant gene CYP2C12 and the
male-dominant CYP2C11 with sex steroid hormones and Cx are consistent
with previous reports of changes with GH secretory patterns
(44); and 4) infusion of GH into male rats
increased ADH-specific activity, protein content, and mRNA to levels
measured in females. Together, the results support an important role
for the differential pattern of GH secretion in the regulation of ADH.
Furthermore, because changes in ADH mRNA and protein were coordinately
expressed, the results are consistent with pretranslational mechanisms
rather than changes in protein turnover (9, 43).
Sexual dimorphic expression of ADH could be due to stimulation by the continuous secretion of GH (female pattern), inhibition by the intermittent malelike pattern, or an interaction of GH with other pituitary hormones. Hx, especially in the male rat, increased ADH activity and mRNA. These results suggested that intermittent GH secretion decreased ADH levels in males, similar to the regulation of S-adenosylmethionine synthetase (46). However, in the Hx rat, intermittent administration of GH only modestly decreased ADH, whereas GH infusions had no significant effect on ADH.
Regulation of CYP genes by pituitary hormones is frequently complex, involving interplay between different hormones. This seemed particularly likely in the regulation of ADH, because several studies have not only implicated GH but glucocorticoids and especially thyroid hormone in regulation of ADH levels (8, 42). Because both glucocorticoids and thyroid hormone can regulate GH levels (62), we examined the effect of these hormone replacements in the Hx male and female rat.
Glucocorticoid administration (data not shown) did not significantly alter ADH levels in Hx rats. Therefore, we then examined T4. Thyroid hormone administration to Hx rats reduced ADH activity and mRNA levels in both sexes but not to basal levels. However, the combination of T4 with intermittent GH administration reduced ADH activity and mRNA to or below basal ADH levels measured in males. This effect was specific for the pattern of GH secretion, because the administration of constant GH infusions with T4 did not significantly alter ADH levels. Furthermore, because the administration of cortisone acetate, in addition to GH and T4, did not contribute to dimorphic expression of ADH (data not shown), T4 and intermittent GH administration are not only specific but also sufficient to lead to sex differences in ADH.
The molecular mechanism(s) accounting for thyroid repression of ADH
either alone or with GH is not clear. A putative thyroid response
element has not been demonstrated in the rat promoter (14), but Harding and Duester (22a)
have demonstrated that thyroid may compete at retinoic acid
receptor elements in the human promoter. However, in the intact
animal, thyroid hormone was also shown to regulate circulating levels
of GH that might, in turn, regulate ADH. Previous reports have
demonstrated that the female-dominant gene, 5-reductase, required
thyroid hormone in addition to GH to increase mRNA to normal levels in
the Hx rat model (53). Although, the molecular mechanism
has not been examined, intermittent GH pulses increase nuclear levels
of signal transducer and activator of transcription (Stat)5b,
resulting in signaling through Stat binding sites. The rat ADH promoter
has a putative Stat response element at
210 bp upstream, which has
been shown to bind Stat5b (48). However, the mechanism
permitting T4 to interact with Stat5b and negatively
regulate ADH gene expression is unknown. One possibility is that
thyroid hormone may inhibit translocation of Stat5 as shown by
Farve-Young et al. (17).
In summary, our experiments demonstrate that neither GH nor thyroid hormone alone can account for the dimorphic expression of hepatic ADH; however, T4 together with the intermittent secretion of GH downregulates ADH, leading to its sexually dimorphic expression. Thus hormonal regulation of ADH provides an excellent model to understand the complex hormonal regulation of a major liver gene that is rate limiting in ethanol oxidation.
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ACKNOWLEDGEMENTS |
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The work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1-DK-15851 and Veterans Affairs Merit Review grants (to F. R. Simon).
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FOOTNOTES |
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Address for reprint requests and other correspondence: F. R. Simon, Dept. of Medicine (B-145), Hepatobiliary Research Center, University of Colorado School of Medicine, 4200 E. 9th Ave., Denver, CO 80262 (E-mail: franz.simon{at}uchsc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpgi.00438.2001
Received 9 October 2001; accepted in final form 17 April 2002.
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