Department of Medicine, University of California San Francisco and Metabolism Section, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, California 94121
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ABSTRACT |
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Infection is associated
with low serum thyroid hormones and thyrotropin levels. Here we
demonstrate that infection also reduces thyroid hormone receptor (TR)
expression. In gel shift experiments, retinoid X receptor (RXR)/TR DNA
binding was reduced in mouse liver by 60 and 77%, respectively, 4 and
16 h after lipopolysaccharide (LPS) administration. Surprisingly,
LPS did not decrease either TR- or TR-
protein levels at 4 h, but by 16 h TR-
1, TR-
2, and
TR-
levels were reduced by 55, 87, and 41%, respectively. We
previously reported that LPS rapidly decreases RXR protein levels in
liver. Therefore, we added RXR-
to hepatic nuclear extracts prepared
4 h after LPS treatment, which restored RXR/TR DNA
binding to a level comparable to that of controls. A similar experiment
conducted on extracts prepared 16 h after LPS administration did
not restore RXR/TR DNA binding. We propose that decreased RXR expression is limiting for RXR/TR DNA binding at
4 h, whereas the reduction in both TR and RXR levels results in
further decreased binding at 16 h.
acute-phase response; thyroid hormone receptor; retinoid X receptor; lipid metabolism
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INTRODUCTION |
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ACUTE NONTHYROIDAL ILLNESSES, such as infection, inflammation, or trauma, result in what is known as the sick euthyroid syndrome (6, 26, 33). The characteristic feature of this syndrome is low triiodothyronine (T3) plasma levels. If the nonthyroidal illness is severe, low serum thyroxine (T4) levels and an inappropriately low normal to subnormal thyrotropin serum concentration may also occur. The pathogenesis of the sick euthyroid syndrome is poorly understood, but both central (pituitary and hypothalamic) and peripheral defects have been proposed. The central defect manifests itself through a low to normal thyrotropin serum secretion despite low T3 and T4 plasma levels. The most commonly described peripheral defect is the reduced conversion of T4 to T3 because of a decrease in 5'-deiodination in the liver.
Injection of bacterial lipopolysaccharide (LPS), which is known to induce the sick euthyroid syndrome (43), triggers a systemic inflammatory response referred to as the acute-phase response (APR), characterized by alterations in hepatic carbohydrate and lipid metabolism. Hypertriglyceridemia, decreased high-density lipoprotein cholesterol levels, and inhibition of bile acid synthesis are among the alterations in lipid metabolism that occur during the APR (15).
The liver plays an important role in thyroid hormone metabolism, and
thyroid hormones, which influence all major metabolic pathways, are
also important regulators of lipid and glucose metabolism in the liver.
T3 has been shown to stimulate the hepatic expression of
genes involved in lipogenesis, such as malic enzyme
(41) and Spot14 (17, 23), and in
bile acid synthesis, such as cholesterol 7-hydroxylase
(Cyp7a; see Ref. 14). Of note, the expression of Cyp7a (12) and of malic enzyme (8) has
previously been shown to be decreased during the APR.
T3 exerts its diverse metabolic effects by binding to
nuclear thyroid hormone receptors (TRs). TRs are encoded by two
homologous but distinct genes, TR- and TR-
,
located on two separate chromosomes. In addition, alternative splicing
from each gene generates multiple TR isoforms, resulting in further
diversity. To date, three T3-binding isoforms of the TR
have been identified, namely TR-
1, TR-
1, and TR-
2. Furthermore, three non-T3-binding
isoforms have been described, the splice variants TR-
2
and TR-
3 and Rev-erbA, which is encoded by
the opposite strand of the TR-
gene. The
TR-
1 isoform is widely expressed, but it is particularly
abundant in liver and kidney (16). In contrast, the
expression of TR-
2 is relatively restricted and is most
highly expressed in the pituitary. TR-
1 and
TR-
2 are abundant in the brain but are also found in most tissues, including heart and liver.
Extensive structural similarities have resulted in the classification of TRs in the type II subfamily of nuclear hormone receptors, which also includes the retinoic acid receptor (RAR), peroxisome proliferator-activated receptors (PPAR), and liver X receptor (LXR; see Ref. 24). These receptors have in common that they heterodimerize with the retinoid X receptor (RXR) for high-affinity binding to DNA. T3-induced gene expression involves binding of RXR/TR heterodimers to specific thyroid hormone response elements (TRE) present in the promoter of the target genes. Three sequence motifs have been shown to function as TRE. These motifs include a direct repeat separated by four nucleotides (DR4), a palindrome called inverted repeat (IR) 0, and an everted repeat separated by six nucleotides (ER6; see Ref. 44).
Several clinical studies evaluating the efficiency of T4 or
T3 administration in the sick euthyroid syndrome have
reported contradictory results, from no benefit to improvement
(6). These results suggested to us that, during the APR, a
reduction in TR expression might occur, decreasing thyroid hormone
responsiveness, thereby participating in the pathophysiology of the
sick euthyroid syndrome. This hypothesis seemed reasonable since our
laboratory and others have shown that treatment with LPS or tumor
necrosis factor (TNF) decreases the expression of another nuclear
hormone receptor, RXR, in hamster liver (3) and rat GH3
cells (37). We also found that the coordinate repression
of RXR and PPAR- could represent one mechanism by which hepatic
fatty acid oxidation is reduced during the APR (3).
Finally, we have previously proposed that the concomitant decrease in
RXR and LXR expression participates in the downregulation of Cyp7a in
liver after LPS administration (3), thereby leading to the
inhibition of bile acid synthesis associated with the APR (12,
27). Thus, to test whether a decrease in TR levels in liver
could participate in the alterations in lipid metabolism that are
associated with infection, we measured TR DNA binding activity and
protein levels in mouse liver after LPS treatment.
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MATERIALS AND METHODS |
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Materials.
LPS (Escherichia coli 55:B5) was obtained from Difco
Laboratories and freshly diluted to a desired concentration in
pyrogen-free 0.9% saline. Oligo(dT)-cellulose type 77F was from
Amersham Pharmacia Biotech. [-32P]dCTP (3,000 Ci/mmol)
and [
-32P]dATP (3,000 Ci/mmol) were purchased from NEN
Life Science Products.
Animals.
All animal studies were conducted in accordance with the highest
standards of humane care and according to the principles and procedures
described in Guidelines for Care and Use of Experimental Animals. Six-week-old female C57BL/6 mice were purchased from Jackson Laboratory. The animals were maintained in a normal-light-cycle room and were provided with rodent chow and water ad libitum. Anesthesia was induced with halothane. To determine the effect of APR
on TR- and TR-
mRNA levels, mice were injected intraperitoneally with 0.1-100 µg LPS in saline or with saline alone. In all other experiments mice were injected intraperitoneally with 100 µg LPS in
saline or with saline alone. Food was withdrawn in all groups at the
time of injection, since LPS induces anorexia in rodents (13). In all experiments, animals were killed between
10:00 and 11:00 AM for the 4-, 16-, and 24-h time points and between 3:00 and 4:00 PM for the 8-h time points. The doses of LPS used in this
study were nonlethal, since the lethal dose 50% (LD50) for
LPS in rodents is ~5 mg/100 g body wt, but they have significant effects on triglyceride and cholesterol metabolism (10,
11).
Measurement of total T3 and total T4 serum levels. Measurements were made on fresh serum, at the time indicated after saline or LPS administration, using Coat-A-Count total T3 and T4 RIA kits (Diagnostic Products).
Preparation of nuclear extracts. Fresh liver (0.5-1 g) was homogenized in 10 mM HEPES (pH 7.9), 25 mM KCl, 0.15 mM spermine, 1 mM EDTA, 2 M sucrose, 10% glycerol, 50 mM NaF, 2 mM sodium metavanadate, 0.5 mM dithiothreitol, and 1% protease inhibitor cocktail (Sigma) 4 and 16 h after LPS or saline treatment. Immediately after homogenization, nuclear proteins were extracted as described previously (3). Nuclear protein content was determined by the Bradford assay (Bio-Rad), and yields were similar in saline- and LPS-treated groups.
Western blot analysis.
Denatured nuclear protein extracts (50 µg) were loaded on 10%
polyacrylamide precast gels (Bio-Rad) and subjected to electrophoresis. After electrotransfer to a polyvinylidene difluoride membrane (Amersham
Pharmacia Biotech), blots were blocked with PBS containing 0.10% Tween
(PBS-T) and 5% dry milk for 1 h at room temperature. Blots were
then incubated for 1 h at room temperature with polyclonal rabbit
antibodies (Affinity BioReagents) raised against human TR- or
TR-
1 (dilution 1:1,000 in PBS-T). Both antibodies were purified from rabbits that had been immunized with a synthetic peptide
whose sequence was derived from the NH2-terminal region of
either human TR-
or human TR-
1 (Affinity
BioReagents). This NH2-terminal region is highly divergent
between TR-
and TR-
isoforms but is identical to the
corresponding rat sequence. Immune complexes were then detected using
horseradish peroxidase-linked donkey anti-rabbit IgG (dilution 1:20,000
in PBS-T) according to the enhanced chemiluminescence plus Western
blotting kit (Amersham Pharmacia Biotech). Immunoreactive bands
obtained by autoradiography were quantified by densitometry.
RNA isolation and Northern blot analysis.
Total RNA was isolated from 150 to 400 mg snap-frozen whole tissue
using Tri-Reagent (Molecular Research Center). Poly(A)+ RNA
was subsequently purified using oligo(dT) cellulose. RNA was quantified
by measuring absorption at 260 nm. Poly(A)+ (10 µg) was
denatured and electrophoresed on a 1% agarose-formaldehyde gel. The
uniformity of sample applications was checked by ultraviolet visualization of the ethidium bromide-stained gel before
electrotransfer to a Nytran membrane (Scleicher & Schuell).
Prehybridization, hybridization, and washing procedures were performed
as described previously (3). Membranes were probed with
[-32P]dCTP-labeled cDNAs using the random priming
technique. RNA levels were detected by exposure of the membrane to
X-ray film and quantified by densitometry. Glyceraldehyde-3-phosphate
dehydrogenase was used as a control probe. Human RXR-
cDNA was a gift from Dr. Daniel D. Bikle (University of California, San
Francisco, CA). Mouse RXR-
and RXR-
cDNAs
were kindly provided by Dr. David J. Mangelsdorf (University of Texas
Southwestern Medical Center, Dallas, TX). The following mouse
probes were generated by RT-PCR starting from total RNA from mouse
liver (ME, Spot14, TR-
1) and heart
(TR-
) and using the following primers: malic enzyme,
5'-CCA CCA GCG CGG CTA CCT GCT GAC GCG GGA-3' (upper) and 5'-CCT CTG ACT CGC CGG TGC CGC AGC CCG ATG-3' (lower; see Ref. 34);
Spot14, 5'-ATG CAA GTG CTA ACG AAA CGC-3' (upper) and 5'-AGA AGT GCA
GGT GGA ACT GGG C-3' (lower; see Ref. 35);
TR-
1, 5'-GCC TGG GAC AAG CAG AAG CCC CGT-3' (upper) and
5'-AGC GAC ATT CCT GGC ACT GGT TGC G-3' (lower; see Refs.
1 and 42); TR-
, 5'-ATG GAA CAG AAG CCA AGC AAG GTG
GAG-3' (upper) and 5'-CTG CAG CAG AGC CAC TTC CGT GTC A-3' (lower).
Electrophoretic gel mobility shift assays.
Nuclear extract (10 µg) was incubated on ice for 30 min with 6 × 104 counts/min 32P-labeled oligonucleotides
in 15 µl binding buffer consisting of 20% glycerol, 25 mM
Tris · HCl (pH 7.5), 40 mM KCl, 0.5 mM MgCl2, 0.1 mM EDTA, 1 mM dithiothreitol, 2 µg
poly(dI-dC), and 1 µg salmon sperm DNA. Double-stranded
oligonucleotide probes were end labeled with T4
polynucleotide kinase in the presence of 50 µCi
[-32P]dATP and purified on a Sephadex G-25 column
(Amersham Pharmacia Biotech). DNA-protein complexes were separated by
electrophoresis (constant voltage of 300 volts) on a 5% nondenaturing
polyacrylamide gel in 0.5× Tris-borate-EDTA at 4°C. Gel was dried,
exposed to X-ray film, and quantified by densitometry. The
following oligonucleotides (upper strand) were used: IR0 (wild type)
5'-GTA CCT CAG GTC ATG ACC TGA C-3' (28); mutated IR0
(mutant) 5'-AGC TTC AGA ACA TGT ACT GAC-3'.
Statistical analysis. Data are expressed as means ± SE of experiments from 3-5 animals/group for each time point. Differences between two experimental groups were analyzed using the unpaired t-test. A P value <0.05 was considered significant.
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RESULTS |
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LPS treatment decreases the expression of TR- target genes in
mouse liver.
Malic enzyme (30, 36) and Spot14
(17, 19, 23, 29) are two well-characterized thyroid
hormone-responsive genes in the liver. Studies in TR-
knockout mice have shown that TR-
is necessary for thyroid
hormone-mediated activation of expression of malic enzyme and Spot14
and for maintaining basal Spot14 mRNA levels
(41). We first tested whether our model of acute
inflammation was associated with a decrease in the level of expression
of malic enzyme and Spot14. As shown in Fig.
1A, 4 h after LPS
administration (100 µg) there was a trend for malic enzyme expression
levels to decrease; these did not reach significance, but by 8 h
we observed a 68% decrease in malic enzyme mRNA levels. A
similar reduction (67%) was observed 16 h after LPS treatment,
and by 24 h malic enzyme mRNA levels were slowly
returning toward normal levels, with a 50% decrease at this time
point. Furthermore, LPS administration (100 µg) was also associated
with a decrease in Spot14 expression, leading to a rapid 61% reduction
in Spot14 mRNA levels within 4 h (Fig. 1B).
A similar 58% decrease in Spot14 mRNA levels was observed
8 h after LPS treatment. By 16 h, Spot14 mRNA
levels were returning toward normal levels, with a modest 3 and 23%
decrease, respectively, 16 and 24 h after LPS administration.
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LPS treatment reduces RXR/TR heterodimers binding to a specific
TRE.
To determine whether the decrease in malic enzyme and
Spot14 mRNA levels could be associated with a reduction in
TR binding to DNA, gel shift experiments were carried out on hepatic
nuclear extracts prepared from mice treated with LPS (100 µg) or with saline. We used a 32P-labeled oligonucleotide containing a
response element more specific for TR, i.e., an inverted repeat (IR) 0 (22, 25) rather than a DR4 (to which LXR and constitutive
androstane receptor can also bind) or an ER6 (also recognized by the
pregnane X receptor). Although TR can bind to its cognate DNA response
element (TRE) as monomers or homodimers, the major form of TR bound to
TRE is the heterodimer with RXR (44). As shown in Fig.
2, A and
B, using an IR0, we detected a strong shifted band in the
samples from saline-treated mice. Competition with cold 100-fold molar excess of the same specific oligonucleotide (wild type) but not of
mutated (mutant) oligonucleotide demonstrated the specificity of the
binding activity we observed in our samples. Furthermore, at 4 h,
LPS administration resulted in a 60% decrease in TR binding activity
in mouse liver nuclear extracts (Fig. 2A). At 16 h, the binding was decreased further, with TR binding activity being reduced
by 77% in nuclear extracts prepared from mice treated with LPS
compared with control mice (Fig. 2B).
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LPS administration decreases TR protein levels at 16 h but not
at 4 h in mouse liver.
We initially determined the effect of LPS treatment on
TR-1 protein levels in mouse liver, since
TR-
1 is the major TR isoform in liver (16).
To examine whether a decrease in TR-
1 protein levels
could account for the reduction in RXR/TR binding
activity as soon as 4 h after LPS administration (100 µg),
Western blot analyses were carried out using nuclear extracts prepared
from mouse liver. As expected (9), a major band
corresponding to a 55-kDa protein was observed with the
TR-
1 antibody (Fig.
3A). Surprisingly, LPS
treatment did not result in a significant decrease in
TR-
1 protein levels at 4 h, but by 16 h LPS
administration was associated with a 41% decrease in
TR-
1 protein levels (Fig. 3A). We then tested
whether the decrease in RXR/TR binding activity we
observed 4 h after LPS treatment could result from a decrease in
TR-
protein levels. As shown in Fig. 3B,
TR-
1 (48 kDa) and TR-
2 (58 kDa) protein
levels were also not significantly reduced 4 h after LPS
administration. On the other hand, 16 h after LPS treatment, there
was a 55 and 87% decrease in TR-
1 and
TR-
2 protein levels, respectively (Fig. 3B).
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LPS-induced RXR repression participates in the reduction in
RXR/TR binding to TRE at 4 h.
To determine whether the decrease in RXR levels we previously described
(3, 4) 4 h after LPS treatment could account for the
reduction in RXR/TR binding at this time point, we next carried out gel shift experiments in which we preincubated liver nuclear extracts from LPS-treated mice with 5, 50, 500, or 5,000 ng
recombinant human RXR- protein. The nuclear extracts were prepared
from mice liver 4 h after injection of LPS (100 µg) or saline
alone. As shown in Fig. 4, adding
increasing quantities of recombinant RXR-
protein to nuclear
extracts prepared from LPS-treated mice (lanes 5-7)
allowed us to dose dependently restore RXR/TR binding up
to the level observed in samples prepared from control mice (lane
2). Beyond 500 ng, further addition of recombinant RXR-
protein
resulted in the binding of recombinant RXR-
protein to the IR0
oligonucleotide as a homodimer (Fig. 4, lane 4). Compared with RXR/TR heterodimers, RXR-
homodimers exhibited
low specificity for the IR0 oligonucleotide, since 100-fold excess of
cold wild-type IR0 only poorly competed with the labeled IR0 probe
(Fig. 4, lane 14).
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LPS treatment decreases the expression level of all TR isoforms in
mouse liver.
To determine whether the decrease in TR protein levels we observed
during the APR is because of a reduction in gene expression, we next
examined the effect of LPS administration on TR mRNA levels. As shown in Fig. 5A, LPS
administration (100 µg) was associated with a time-dependent decrease
in TR-1 expression levels in mouse liver.
TR-
1 mRNA levels were decreased by 45%
4 h after LPS treatment. By 8 h, LPS administration induced a
marked 83% reduction in TR-
1 mRNA levels,
and this effect was maintained for at least 16 h (89% decrease at
16 h after LPS treatment). But by 24 h
TR-
1 mRNA levels were slowly returning toward
normal levels, with LPS treatment leading to a more modest 68%
reduction in TR-
1 mRNA levels at this time
point. Furthermore, at 16 h, the LPS-induced decrease in
TR-
1 mRNA levels was dose dependent, with a
half-maximum effect occurring at ~7 µg LPS (data not shown).
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DISCUSSION |
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Infection, inflammation, and trauma are known to induce changes in
metabolism, which are part of the pathophysiology of the APR. In the
liver, the synthesis of certain proteins is increased (positive
acute-phase proteins), such as C-reactive protein (which is thought to
play a protective role during infection; see Ref. 38),
whereas the synthesis of other proteins (negative acute-phase proteins)
is decreased (20). Several negative acute-phase proteins are involved in lipid metabolism, and the decrease in expression of
these proteins leads to many changes during the APR, including a
decrease in hepatic fatty acid oxidation, ketogenesis, and bile acid
synthesis (15). During the APR, most of the changes in hepatic protein expression are thought to occur at the transcriptional level. The mechanism by which gene transcription is stimulated during
the APR has been studied extensively. Transcription factors such as
CCAAT/enhancer binding protein, nuclear transcription factor-B, and
members of the signal transducer and activator of transcription family
are thought to mediate the increase in expression of most positive
acute-phase proteins (2). On the other hand,
downregulation of members of the nuclear hormone receptor superfamily,
including hepatic nuclear factor 4 (31), PPAR
(3), LXR (3), and RAR (7), is
thought to be involved in the repression of several negative
acute-phase proteins.
We therefore determined whether TR, a member of the nuclear hormone receptor superfamily, could be downregulated during the APR, thereby representing one possible mechanism by which malic enzyme and Spot14 are repressed in our model of inflammation. Our experiments do not rule out the possibility that other molecular mechanisms are involved in the decrease in expression of these two proteins during the APR. Another transcription factor, sterol regulatory element-binding protein-1 (SREBP-1), has been identified as a key activator of malic enzyme and Spot14 during fasting-refeeding treatments (34). However, it is unlikely that SREBP-1 plays a role in the downregulation of these enzymes during the APR, since the proinflammatory cytokine TNF has been shown to actually stimulate the maturation of SREBP-1 in hepatocytes (21). Finally, our experiments do not exclude the possibility that LPS decreases the expression of malic enzyme and Spot14 at the posttranscriptional level. Unfortunately, RNA degradation studies typically use actinomycin D, a compound that dramatically increases LPS toxicity, rendering the interpretation of the results difficult.
Here we show that a time-dependent decrease in TR- protein and mRNA
levels occurs in mouse liver, suggesting that TR-
repression is at
least in part the result of a decrease in protein synthesis after LPS
administration. Furthermore, the LPS-induced decrease in TR-
, the
major isoform in the liver, was not compensated by an upregulation of
TR-
. On the contrary, TR-
protein and mRNA levels were markedly
decreased after LPS treatment. We also report a reduction in TR DNA
binding in mouse liver during the APR. However, the reduction in TR DNA
binding preceded the decrease in TR protein levels.
Of note, the decrease in TR DNA binding even preceded the hereby and previously described (5) LPS-induced decrease in thyroid hormone circulating levels. In our hands, serum T3 levels were unaffected at least for the first 16 h after LPS treatment, whereas serum T4 levels started to decline 16 h after LPS administration.
TR forms heterodimers with RXR for high-affinity binding to DNA
(22). Because we have already shown that all three RXR
isoforms (RXR-, -
, and -
) are downregulated at the protein
level as early as 4 h after LPS treatment (3), we
hypothesized that the early decrease in RXR availability in liver might
play an important role in the decrease in TR DNA binding at 4 h.
Our results suggest that this might be the case, since adding
recombinant RXR-
to these extracts restored TR DNA binding at least
partially at this early time point. These findings are consistent with
previous studies (18, 32) in which others showed that
PPAR-
can inhibit RXR/TR DNA binding by "titering"
out RXR. Although the mechanism of reduction is different, since
PPAR-
is actually downregulated during the APR (3),
both their experiments and ours imply that RXR availability could limit
TR DNA binding. On the other hand, our findings are in apparent
contradiction with observations in hepatocyte-specific
RXR-
-deficient mice (40). Using a cre/loxP recombination technique, these authors reported that the deletion of
RXR-
specifically in the liver did not affect malic
enzyme basal mRNA levels. However, as suggested by our
electrophoretic mobility shift assay experiments, TR also forms
heterodimers with RXR-
. It is conceivable that, in the setting of
RXR-
deficiency, RXR-
/TR and/or RXR-
/TR heterodimers could
play a role in maintaining basal level of key enzymes such as malic
enzyme, which constitute a major source of NADPH in hepatocytes
(39). In our model of inflammation, however, such
compensatory mechanism could not occur, since all three RXR isoforms
are repressed in the liver. At the later time point (16 h), the
coordinate downregulation of both RXR and TR resulted in further
reduction in TR DNA binding, which could not significantly be corrected
by an excess amount of recombinant RXR-
. Therefore, our results
suggest that the time-dependent decrease in TR DNA binding that we
observed in mouse liver after LPS administration results from a dual
mechanism. The early decrease in RXR levels seems to play a critical
role in the reduction in binding at 4 h, suggesting that, even in
the setting of nonpermissive heterodimers, such as RXR/TR
heterodimers, the silent partner RXR could constitute a target for fine
regulation of the pathway. In contrast, at the later time point, a
decrease in both TR and RXR levels results in a further reduction in TR
DNA binding.
Overall, the changes in TR and RXR levels that occur during the APR will limit the impact of T3 in liver. Whether this effect constitutes a physiological or a pathological response to infection and inflammation remains unclear. On one hand, because the APR is associated with an increased metabolic rate, a reduction in T3 activity may improve survival by conserving energy, limiting hepatic proteolysis and catabolism. On the other hand, critically ill patients exhibiting the severe form of sick euthyroid syndrome have a worse prognosis. It would be of interest to determine whether a reduction in TR and/or RXR levels also occurs in the heart during the APR, since such an effect could increase the mortality risk by decreasing cardiac function. In summary, the APR results in a time-dependent decrease in TR protein, mRNA, and DNA binding activity in mouse liver. These changes occur in the early phases of the inflammatory response, providing an additional level of regulation of thyroid hormone action during infection.
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ACKNOWLEDGEMENTS |
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This work was supported by grants from the Research Service of the Department of Veterans Affairs and by National Institutes of Health Grants DK-49448 and AR-39639.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. P. Beigneux, Gladstone Institute of Cardiovascular Disease, P. O. Box 419100, San Francisco, CA 94141-9100 (E-mail: abeigneux{at}gladstone.ucsf.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.
September 3, 2002;10.1152/ajpendo.00155.2002
Received 11 April 2002; accepted in final form 28 August 2002.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Abel, ED,
Boers ME,
Pazos-Moura C,
Moura E,
Kaulbach H,
Zakaria M,
Lowell B,
Radovick S,
Liberman MC,
and
Wondisford F.
Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system.
J Clin Invest
104:
291-300,
1999
2.
Baumann, H,
and
Gauldie J.
The acute phase response.
Immunol Today
15:
74-80,
1994[ISI][Medline].
3.
Beigneux, AP,
Moser AH,
Shigenaga JK,
Grunfeld C,
and
Feingold KR.
The acute phase response is associated with retinoid X receptor repression in rodent liver.
J Biol Chem
275:
16390-16399,
2000
4.
Beigneux, AP,
Moser AH,
Shigenaga JK,
Grunfeld C,
and
Feingold KR.
Reduction in cytochrome P-450 enzyme expression is associated with repression of CAR (constitutive androstane receptor) and PXR (pregnane X receptor) in mouse liver during the acute phase response.
Biochem Biophys Res Commun
293:
145-149,
2002[ISI][Medline].
5.
Boelen, A,
Platvoet-ter Schiphorst MC,
Bakker O,
and
Wiersinga WM.
The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice.
J Endocrinol
146:
475-483,
1995[Abstract].
6.
Chopra, IJ.
Clinical review 86: euthyroid sick syndrome: is it a misnomer?
J Clin Endocrinol Metab
82:
329-334,
1997
7.
Denson, LA,
Auld KL,
Schiek DS,
McClure MH,
Mangelsdorf DJ,
and
Karpen SJ.
Interleukin-1beta suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation.
J Biol Chem
275:
8835-8843,
2000
8.
Diez-Fernandez, C,
Sanz N,
and
Cascales M.
Changes in glucose-6-phosphate dehydrogenase and malic enzyme gene expression in acute hepatic injury induced by thioacetamide.
Biochem Pharmacol
51:
1159-1163,
1996[ISI][Medline].
9.
Falcone, M,
Miyamoto T,
Fierro-Renoy F,
Macchia E,
and
DeGroot LJ.
Antipeptide polyclonal antibodies specifically recognize each human thyroid hormone receptor isoform.
Endocrinology
131:
2419-2429,
1992[Abstract].
10.
Feingold, KR,
Hardardottir I,
Memon R,
Krul EJ,
Moser AH,
Taylor JM,
and
Grunfeld C.
Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters.
J Lipid Res
34:
2147-2158,
1993[Abstract].
11.
Feingold, KR,
Pollock AS,
Moser AH,
Shigenaga JK,
and
Grunfeld C.
Discordant regulation of proteins of cholesterol metabolism during the acute phase response.
J Lipid Res
36:
1474-1482,
1995[Abstract].
12.
Feingold, KR,
Spady DK,
Pollock AS,
Moser AH,
and
Grunfeld C.
Endotoxin, TNF, and IL-1 decrease cholesterol 7 alpha-hydroxylase mRNA levels and activity.
J Lipid Res
37:
223-228,
1996[Abstract].
13.
Grunfeld, C,
Zhao C,
Fuller J,
Pollack A,
Moser A,
Friedman J,
and
Feingold KR.
Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters.
J Clin Invest
97:
2152-2157,
1996
14.
Gullberg, H,
Rudling M,
Forrest D,
Angelin B,
and
Vennstrom B.
Thyroid hormone receptor beta-deficient mice show complete loss of the normal cholesterol 7alpha-hydroxylase (CYP7A) response to thyroid hormone but display enhanced resistance to dietary cholesterol.
Mol Endocrinol
14:
1739-1749,
2000
15.
Hardardottir, I,
Grunfeld C,
and
Feingold KR.
Effects of endotoxin on lipid metabolism.
Biochem Soc Trans
23:
1013-1018,
1995[ISI][Medline].
16.
Hodin, RA,
Lazar MA,
and
Chin WW.
Differential and tissue-specific regulation of the multiple rat c-erbA messenger RNA species by thyroid hormone.
J Clin Invest
85:
101-105,
1990[ISI][Medline].
17.
Jacoby, DB,
Engle JA,
and
Towle HC.
Induction of a rapidly responsive hepatic gene product by thyroid hormone requires ongoing protein synthesis.
Mol Cell Biol
7:
1352-1357,
1987[ISI][Medline].
18.
Juge-Aubry, CE,
Gorla-Bajszczak A,
Pernin A,
Lemberger T,
Wahli W,
Burger AG,
and
Meier CA.
Peroxisome proliferator-activated receptor mediates cross-talk with thyroid hormone receptor by competition for retinoid X receptor. Possible role of a leucine zipper-like heptad repeat.
J Biol Chem
270:
18117-18122,
1995
19.
Jump, DB,
Narayan P,
Towle H,
and
Oppenheimer JH.
Rapid effects of triiodothyronine on hepatic gene expression. Hybridization analysis of tissue-specific triiodothyronine regulation of mRNAS14.
J Biol Chem
259:
2789-2797,
1984
20.
Kushner, I.
The phenomenon of the acute phase response.
Ann NY Acad Sci
389:
39-48,
1982[ISI][Medline].
21.
Lawler, JF, Jr,
Yin M,
Diehl AM,
Roberts E,
and
Chatterjee S.
Tumor necrosis factor-alpha stimulates the maturation of sterol regulatory element binding protein-1 in human hepatocytes through the action of neutral sphingomyelinase.
J Biol Chem
273:
5053-5059,
1998
22.
Leid, M,
Kastner P,
Lyons R,
Nakshatri H,
Saunders M,
Zacharewski T,
Chen JY,
Staub A,
Garnier JM,
and
Mader S.
Purification, cloning, and RXR identity of the HeLa cell factor with which RAR or TR heterodimerizes to bind target sequences efficiently.
Cell
68:
377-395,
1992[ISI][Medline].
23.
Liu, HC,
and
Towle HC.
Functional synergism between multiple thyroid hormone response elements regulates hepatic expression of the rat S14 gene.
Mol Endocrinol
8:
1021-1037,
1994[Abstract].
24.
Mangelsdorf, DJ,
and
Evans RM.
The RXR heterodimers and orphan receptors.
Cell
83:
841-850,
1995[ISI][Medline].
25.
Mangelsdorf, DJ,
Thummel C,
Beato M,
Herrlich P,
Schutz G,
Umesono K,
Blumberg B,
Kastner P,
Mark M,
and
Chambon P.
The nuclear receptor superfamily: the second decade.
Cell
83:
835-839,
1995[ISI][Medline].
26.
Monig, H,
Arendt T,
Meyer M,
Kloehn S,
and
Bewig B.
Activation of the hypothalamo-pituitary-adrenal axis in response to septic or non-septic diseasesimplications for the euthyroid sick syndrome.
Intensive Care Med
25:
1402-1406,
1999[ISI][Medline].
27.
Moseley, RH.
Sepsis-associated cholestasis.
Gastroenterology
112:
302-306,
1997[ISI][Medline].
28.
Nagaya, T,
Madison LD,
and
Jameson JL.
Thyroid hormone receptor mutants that cause resistance to thyroid hormone. Evidence for receptor competition for DNA sequences in target genes.
J Biol Chem
267:
13014-13019,
1992
29.
Narayan, P,
Liaw CW,
and
Towle HC.
Rapid induction of a specific nuclear mRNA precursor by thyroid hormone.
Proc Natl Acad Sci USA
81:
4687-4691,
1984[Abstract].
30.
Petty, KJ,
Morioka H,
Mitsuhashi T,
and
Nikodem VM.
Thyroid hormone regulation of transcription factors involved in malic enzyme gene expression.
J Biol Chem
264:
11483-11490,
1989
31.
Reddy, S,
Yang W,
Taylor DG,
Shen X,
Oxender D,
Kust G,
and
Leff T.
Mitogen-activated protein kinase regulates transcription of the ApoCIII gene. Involvement of the orphan nuclear receptor HNF4.
J Biol Chem
274:
33050-33056,
1999
32.
Ren, B,
Thelen A,
and
Jump DB.
Peroxisome proliferator-activated receptor alpha inhibits hepatic S14 gene transcription. Evidence against the peroxisome proliferator-activated receptor alpha as the mediator of polyunsaturated fatty acid regulation of s14 gene transcription.
J Biol Chem
271:
17167-17173,
1996
33.
Sellmeyer, DE,
and
Grunfeld C.
Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome.
Endocr Rev
17:
518-532,
1996[Abstract].
34.
Shimano, H,
Yahagi N,
Amemiya-Kudo M,
Hasty AH,
Osuga J,
Tamura Y,
Shionoiri F,
Iizuka Y,
Ohashi K,
Harada K,
Gotoda T,
Ishibashi S,
and
Yamada N.
Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes.
J Biol Chem
274:
35832-35839,
1999
35.
Shimomura, I,
Shimano H,
Korn BS,
Bashmakov Y,
and
Horton JD.
Nuclear sterol regulatory element-binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver.
J Biol Chem
273:
35299-35306,
1998
36.
Song, MK,
Dozin B,
Grieco D,
Rall JE,
and
Nikodem VM.
Transcriptional activation and stabilization of malic enzyme mRNA precursor by thyroid hormone.
J Biol Chem
263:
17970-17974,
1988
37.
Sugawara, A,
Uruno A,
Nagata T,
Taketo MM,
Takeuchi K,
and
Ito S.
Characterization of mouse retinoid X receptor (RXR)-beta gene promoter: negative regulation by tumor necrosis factor (TNF)-alpha.
Endocrinology
139:
3030-3033,
1998
38.
Szalai, AJ,
Briles DE,
and
Volanakis JE.
Human C-reactive protein is protective against fatal Streptococcus pneumoniae infection in transgenic mice.
J Immunol
155:
2557-2563,
1995[Abstract].
39.
Towle, HC,
Kaytor EN,
and
Shih HM.
Regulation of the expression of lipogenic enzyme genes by carbohydrate.
Annu Rev Nutr
17:
405-433,
1997[ISI][Medline].
40.
Wan, YJ,
Cai Y,
Lungo W,
Fu P,
Locker J,
French S,
and
Sucov HM.
Peroxisome proliferator-activated receptor alpha-mediated pathways are altered in hepatocyte-specific retinoid X receptor alpha-deficient mice.
J Biol Chem
275:
28285-28290,
2000
41.
Weiss, RE,
Murata Y,
Cua K,
Hayashi Y,
Seo H,
and
Refetoff S.
Thyroid hormone action on liver, heart, and energy expenditure in thyroid hormone receptor beta-deficient mice.
Endocrinology
139:
4945-4952,
1998
42.
Wood, WM,
Ocran KW,
Gordon DF,
and
Ridgway EC.
Isolation and characterization of mouse complementary DNAs encoding alpha and beta thyroid hormone receptors from thyrotrope cells: the mouse pituitary-specific beta 2 isoform differs at the amino terminus from the corresponding species from rat pituitary tumor cells.
Mol Endocrinol
5:
1049-1061,
1991[Abstract].
43.
Yu, J,
and
Koenig RJ.
Regulation of hepatocyte thyroxine 5'-deiodinase by T3 and nuclear receptor coactivators as a model of the sick euthyroid syndrome.
J Biol Chem
275:
38296-38301,
2000
44.
Zhang, J,
and
Lazar MA.
The mechanism of action of thyroid hormones.
Annu Rev Physiol
62:
439-466,
2000[ISI][Medline].