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Originally published In Press as doi:10.1074/jbc.M000953200 on March 21, 2000
J. Biol. Chem., Vol. 275, Issue 21, 16390-16399, May 26, 2000
The Acute Phase Response Is Associated with Retinoid X
Receptor Repression in Rodent Liver*
Anne P.
Beigneux,
Arthur H.
Moser,
Judy K.
Shigenaga,
Carl
Grunfeld, and
Kenneth R.
Feingold
From the Department of Medicine, University of California San
Francisco, Metabolism Section, Medical Service, Department of Veterans
Affairs Medical Center, San Francisco, California 94121
Received for publication, February 6, 2000, and in revised form, March 17, 2000
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ABSTRACT |
The acute phase response (APR) is associated with
decreased hepatic expression of many proteins involved in lipid
metabolism. The nuclear hormone receptors peroxisome
proliferator-activated receptor (PPAR ) and liver X receptor
(LXR) play key roles in regulation of hepatic lipid metabolism. Because
heterodimerization with RXR is crucial for their action, we
hypothesized that a decrease in RXR may be one mechanism to
coordinately down-regulate gene expression during APR. We demonstrate
that lipopolysaccharide (LPS) induces a rapid,
dose-dependent decrease in RXR , RXR , and RXR
proteins in hamster liver. Maximum inhibition was observed at 4 h
for RXR (62%) and RXR (50%) and at 2 h for RXR (61%). These decreases were associated with a marked reduction in RXR , RXR , and RXR mRNA levels. Increased RNA degradation is likely responsible for the repression of RXR, because LPS did not decrease RXR and RXR transcription and only
marginally inhibited (38%) RXR transcription. RXR
repression was associated with decreased LXR and PPAR mRNA
levels and reduced RXR·RXR, RXR·PPAR and RXR·LXR binding
activities in nuclear extracts. Furthermore, LPS markedly decreased
both basal and Wy-14,643-induced expression of acyl-CoA synthetase, a
well characterized PPAR target. The reduction in hepatic RXR levels
alone or in association with other nuclear hormone receptors could be a
mechanism for coordinately inhibiting the expression of multiple genes
during the APR.
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INTRODUCTION |
Small lipophilic compounds, such as steroids, thyroid hormones,
vitamin D, and retinoids, regulate gene expression by binding to
nuclear hormone receptors (1-3). Nuclear hormone receptors are the
largest known family of transcription factors, with over 150 members
currently. The nuclear hormone receptors share a common structural
composition, including a central, highly conserved DNA-binding domain
and a carboxyl-terminal domain that mediates ligand recognition,
receptor dimerization, and ligand-dependent activation
(1-3).
The nuclear receptor superfamily has been divided into four major
subgroups according to their dimerization and DNA binding properties
(3). Class II receptors consist of nuclear receptors that
heterodimerize with the retinoid X receptor
(RXR)1 and usually bind to
direct repeats separated by a variable number of spacer nucleotides (3,
4). The class II subgroup includes the retinoic acid receptor (RAR),
thyroid hormone receptor, vitamin D receptor, farnesoid X receptor,
peroxisome proliferator-activated receptor (PPAR), and liver X receptor
(LXR) (3, 5). Three distinct RXR genes have been cloned:
RXR , RXR , and RXR . RXR is
strongly expressed in liver, kidney, muscle, lung, and spleen (6, 7).
RXR is also present in the brain and heart (6, 7). RXR is
expressed ubiquitously, and it is present at low level in liver,
intestine, and testis (6, 7). RXR is expressed only in liver,
kidney, muscle, brain, heart, and adrenal (6, 7). To date, the 9-cis
retinoic acid isomer has been identified as the most potent endogenous
ligand for RXR (8).
The acute phase response (APR), which is induced during infection,
inflammation, and injury, is associated with numerous changes in lipid
metabolism (9). Hypertriglyceridemia, decreased high density
lipoprotein cholesterol levels, accelerated lipolysis, decreased
hepatic fatty acid (FA) oxidation, and inhibition of the synthesis of
bile acids are some of the alterations in lipid metabolism that occur
during the APR (9). In most instances, these changes are mediated by
pro-inflammatory cytokines such as tumor necrosis factor (TNF) or
interleukin (IL)-1 and are due to alterations in gene transcription
(9). However, the molecular mechanisms underlying these alterations in
gene transcription that account for the changes in lipid metabolism
during the APR remain to be identified.
Both PPAR and LXR have been implicated in the regulation of genes
important in lipid metabolism. PPAR activation in the liver stimulates FA metabolism and transport, and LXR activation leads to an
increase in bile acid synthesis. Specifically, PPAR increases the
expression of carnitine palmitoyltransferase I,
3-hydroxy-3-methylglutaryl-CoA synthase, acyl-CoA oxidase, acyl-CoA
synthetase (ACS), cytochrome P450 4A enzymes, FA transport protein, and
FA-binding protein (10-17). Furthermore, LXR stimulates the expression
of 7 -hydroxylase gene (CYP7A), the rate-limiting enzyme
for conversion of cholesterol to bile acids (18, 19). Studies in our
laboratory (20-24) and others (25, 26) have shown that the expression
or activity of each of these proteins involved in lipid metabolism in
the liver is rapidly and markedly decreased following induction of the
APR by LPS or cytokine administration.
One potential mechanism by which the expression of many genes could be
coordinately decreased during the APR is by the reduction of the levels
of specific transcription factors. Because heterodimerization with RXR
is crucial for the action of several nuclear hormone receptors
including PPAR and LXR, we hypothesized that a decrease in RXR levels
in the liver may occur during APR. Previous studies by Sugawara
et al. (27) showed that TNF decreases the expression of a
RXR promoter construct in rat GH3 cells. Here we report that RXR , RXR , and RXR proteins and mRNA levels decline
during the APR in hamster. RXR repression is associated with LXR and PPAR repression, resulting in an overall decreased ability of RXR·RXR homodimers, RXR·PPAR, and RXR·LXR heterodimers to bind to
their respective response elements.
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EXPERIMENTAL PROCEDURES |
Materials--
LPS (Escherichia coli 55:B5) was
obtained from Difco Laboratories and freshly diluted to desired
concentration in pyrogen-free 0.9% saline. Human TNF- (specific
activity, 5 × 107 units/mg) was provided by
Genentech, Inc. Recombinant human IL-1 (specific activity, 4 × 108 units/mg) was a gift from Dr. Charles A. Dinarello
(University of Colorado, Denver, CO). The cytokines were freshly
diluted to desired concentrations in pyrogen-free 0.9% saline
containing 0.1% human serum albumin. Oligo(dT)-cellulose type 77F was
from Amersham Pharmacia Biotech. Wy-14,643 was purchased from Sigma and
freshly resuspended in corn oil at the appropriate concentration. [ -32P]dCTP (3,000 Ci/mmol),
[ -32P]dATP (3,000 Ci/mmol), and
[ -32P]dUTP (800 Ci/mmol) were purchased from NEN Life
Science Products.
Animals--
Male Syrian hamsters (140-160 g) were purchased
from Simonsen Laboratories (Gilroy, CA). 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 assess the effect of the acute phase response on RXR, hamsters were injected intraperitoneally with 0.1-100 µg/100 g of body weight (BW) LPS, 25 µg/100 g of BW TNF- , or 1 µg/100 g of BW IL-1 in 0.5 ml of saline or with saline alone. To assess the effect of LPS treatment on
PPAR activation, hamsters were injected IP daily with Wy-14,643 at a
dosage of 5 mg/100 g of BW or with corn oil alone for 5 days. On the
fifth day, 100 µg/100 g of BW LPS or saline alone was administered IP. Food was withdrawn at the time of injection because LPS and cytokines induce marked anorexia in rodents (28). Livers were removed
after treatment at the times indicated below. The doses of LPS used in
this study have significant effects on triglyceride and cholesterol
metabolism without causing death (23, 29). Similarly, the nonlethal
doses of TNF- and IL-1 used in this study reproduce many of the
effects of LPS on lipid metabolism, causing marked changes in serum
lipid and lipoprotein levels (9, 30).
Preparation of Nuclear Extracts--
Fresh liver (1.5-2 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 mixture (Sigma) at the times indicated below after LPS or
saline treatment. Immediately following homogenization, nuclear
proteins were extracted as described by Neish et al. (31), except that 1 mM NaF, 0.1 mM metavanadate, and
1% protease inhibitor mixture (Sigma) were added to all buffers.
Nuclear protein content was determined by the Bradford assay (Bio-Rad),
and yields were similar in control and LPS-treated groups.
Western Blot Analysis--
Denatured nuclear protein (25 µg)
was loaded onto 10% polyacrylamide precast gels (Bio-Rad) and
subjected to electrophoresis. After electrotransfer onto polyvinylidene
difluoride membrane (Amersham Pharmacia Biotech), blots were blocked
with phosphate-buffered saline containing 0.10% Tween and 5% dry milk
for 1 h at room temperature and incubated for 1 h at room
temperature with the following polyclonal rabbit antibodies (Santa Cruz
Biotechnology) at a dilution of 1:5000: anti-RXR , anti-RXR , and
anti-RXR . Immune complexes were detected using horseradish
peroxidase-linked donkey anti-rabbit IgG (dilution 1:20,000) according
to the ECL 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 300-400 mg of snap-frozen whole liver tissue by a
modified acid guanidinium thiocyanate-phenol-chloroform method (32) as
described earlier (21). Poly(A)+ RNA was purified using oligo(dT)
cellulose and quantified by measuring absorption at 260 nm. Ten
micrograms of poly(A)+ or 20 µg of total RNA were denatured and
electrophoresed on a 1% agarose/formaldehyde gel. The uniformity of
sample applications was checked by UV visualization of the acridine
orange-stained gel before electrotransfer to Nytran membrane
(Schleicher & Schuell), or when indicated, p18S was used as a control
probe. We and others have found that LPS increases actin mRNA
levels in liver by 2-5-fold in rodents (29, 33). TNF and IL-1 produced
a 2-fold increase in actin mRNA levels. LPS also produces a 2-fold
increase in glyceraldehyde-3-phosphate dehydrogenase and a 2.6-fold
increase in cyclophilin mRNA (20). Thus, the mRNA levels of
actin, glyceraldehyde-3-phosphate dehydrogenase, and cyclophilin, which
are widely used to normalize data, cannot be used to study LPS or
cytokine-induced regulation of proteins in liver. However, the
differing direction of the changes in mRNA levels for specific
proteins after LPS or cytokine administration, the magnitude of the
alterations, and the relatively small standard error of the mean make
it unlikely that the changes observed were due to unequal loading of
mRNA (20, 23, 24, 29, 34). Prehybridization, hybridization, and
washing procedures were performed as described previously (21).
Membranes were probed with [ -32P]dCTP labeled
cDNAs using the random priming technique. mRNA levels were
detected by exposure of the membrane to x-ray film and quantified by
densitometry. hRXR cDNA was a gift from Dr. Daniel D. Bikle
(University of California, San Francisco, CA). mouse RXR , mouse
RXR , human LXR , and human LXR cDNAs were kindly provided
by Dr. David J. Mangelsdorf (University of Texas Southwestern Medical
Center, Dallas, TX). RACS cDNA was kindly provided by Dr. Pamela J. Smith (Ross Products Division, Abbott Laboratories, Columbus, OH).
rPPAR , mPPAR , and mPPAR cDNAs were a gift from Dr. Anthony
Bass (University of California San Francisco, CA).
Nuclear Run-on Transcription Assay--
Isolation of liver
nuclei from fresh tissue, the procedure for in vitro nuclear
transcription and hybridization was essentially as described by Clarke
et al. (35). Briefly, nuclei were incubated with 200 µCi
of [ -32P]UTP, and after labeling nascent transcripts
for 30 min at 30 °C, total RNA was recovered according to
Chomczynski and Sacchi (32). After prehybridization, all of the
in vitro labeled RNA isolated (2-9 × 106
cpm total) from nuclei of control and LPS-treated hamsters were hybridized to prepared nylon membrane (Schleicher & Schuell). After
being washed and autoradiographed, the filters were air-dried, and the
amount of in vitro labeled RNA that hybridized to each dot
containing 10 µg of cDNA for RXR , RXR , RXR , actin, and vector pUC19 was measured by liquid scintillation counting.
Electrophoretic Gel Mobility Shift Assays--
10 µg of crude
nuclear extract were incubated on ice for 30 min with 6 × 104 cpm of 32P-labeled oligonucleotides in 15 µl of binding buffer (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 of
poly(dI-dC), and 1 µg of salmon sperm DNA. Double-stranded
oligonucleotide probes were end-labeled with
T4-polynucleotide kinase in presence of 50 µCi of
[ -32P]dATP and purified on a Sephadex G-25 column
(Amersham Pharmacia Biotech), and the LXR oligonucleotide was
subsequently gel-purified. DNA-protein complexes were separated by
electrophoresis (constant voltage of 300 V) on a 5% nondenaturing
polyacrylamide gel in 1× TBE at 4 °C. The gel was dried, exposed to
x-ray film, and quantified by densitometry. In the competition assay, a
100-fold molar excess of the specific or mutated unlabeled
oligonucleotide was preincubated on ice for 1 h with 10 µg of
nuclear extract from control hamster in the binding buffer before
adding the oligonucleotide probe. The following oligonucleotides were
used: PPAR response element, 5'-GATCCTCCCGAACGTGACCTTTGTCCTGGTCCA-3'
(36); mut-PPAR response element,
5'-GATCCTCCCGAACGCAGCTGTCAGCTGGGTCCA-3'; CRBPII, 5'-GATACTGCTGTCACAGGTCACAGGTCACAGTTCAA-3' (36); (37, 38); mut-CRBPII, 5'-GATACTGCTGTCACAGCACACAGCACACAGTTCAA-3'; CYP7-LXR response element, 5'-GATCCCTTTGGTCACTCAAGTTCAAGTGGATC-3' (18); and mut-CYP7-LXR response element,
5'-GATCCCTTTGGTCACTCAAGAACAAGTGGATC-3' (18). In supershift studies,
control nuclear extract was preincubated with 2 µl of one of the
following antibodies (Santa Cruz Biotechnology) for 1 h at room
temperature prior to the addition of the labeled probe: anti-RXR ,
anti-RXR , anti-RXR , and anti-rabbit IgG.
Statistical Analysis--
Data are expressed as mean ± S.E. of experiments from 3-5 animals per group for each time point.
The difference between two experimental groups was analyzed using the
unpaired t test. Differences among multiple groups were
analyzed using one-way analysis of variance with the Dunnett's
post-test correction. A p value < 0.05 was considered significant.
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RESULTS |
LPS and Cytokines Decrease RXR Levels--
We initially determined
the effect of LPS administration on RXR protein levels in the nuclei
from liver of Syrian hamsters. RXR is the most abundant RXR isoform
in liver. As shown in Fig. 1A,
LPS (100 µg/100 g of BW) produced a maximum decrease (62%) in RXR
protein levels at 4 h. A similar decrease was also present at
8 h following LPS treatment, but by 16 h, RXR protein was returning toward normal levels (23% decrease at 16 h). As shown in Fig. 2A, the LPS-induced
decrease in RXR protein levels was dose-dependent, with
the half-maximal effect occurring at approximately 2 µg/100 g of BW.
Thus, LPS at relatively low doses (LD50 for LPS in rodents
is approximately 5 mg/100 g of BW) rapidly decreases RXR protein
levels in the liver of Syrian hamsters.

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Fig. 1.
Time course of the regulation by LPS of
RXR (A),
RXR (B), and
RXR (C) proteins in hamster
liver. Syrian hamsters were injected IP with either saline or LPS
(100 µg of LPS/100 g of BW), and the animals were sacrificed at the
time indicated after LPS administration. Hepatic nuclear extracts were
prepared, and Western blot analysis was carried out as described under
"Experimental Procedures." Data (means ± S.E.,
n = 5) are expressed as a percentage of controls. *,
p < 0.05; ***, p < 0.005 versus control.
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Fig. 2.
Dose response of the regulation by LPS of
RXR (A),
RXR (B), and
RXR (C) proteins in hamster
liver. Syrian hamsters were injected IP with either saline or LPS
at the doses indicated, and the animals were sacrificed 4 h after
LPS administration. Hepatic nuclear extracts were prepared, and Western
blot analysis was carried out as described under "Experimental
Procedures." Data (means ± S.E., n = 5) are
expressed as a percentage of controls. **, p < 0.01;
***, p < 0.005 versus control.
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We next determined whether this decrease in RXR protein levels was
associated with alterations in RXR mRNA levels in the liver. As
shown in Fig. 3A, LPS
administration resulted in a marked reduction (97%) in RXR mRNA
levels in the liver of Syrian hamsters at 4 h. To determine
whether this decrease in mRNA levels was due to an inhibition of
transcription, nuclear run-on assays were performed on nuclei prepared
from hamster liver 4 h after LPS or saline injection. As shown in
Fig. 4A, LPS treatment
resulted in a 38% decrease in RXR transcription compared
with control. Therefore, the decrease in RXR protein levels
following LPS administration is associated with a decrease in mRNA
levels that is partially accounted for by LPS inhibition of
RXR gene transcription. However, the modest reduction in
transcription compared with the marked decrease in mRNA levels
suggests that post-transcriptional factors in addition to inhibition of
transcription contribute to the LPS-induced decrease in RXR mRNA
levels.

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Fig. 3.
Effect of LPS (A) or
cytokine (B) treatment on
RXR , RXR , and
RXR mRNA levels in hamster liver.
Syrian hamsters were injected IP with either saline, LPS (100 µg of
LPS/100 g of BW), TNF (25 µg/100 g of BW), IL-1 (1 µg/100 g of BW),
or TNF plus IL-1. Four hours after LPS treatment (A) or
2 h after cytokine treatment (B), livers were removed,
and poly(A)+ RNA and Northern blots were prepared as described under
"Experimental Procedures." Data (means ± S.E.,
n = 4-5) are expressed as a percentage of controls. *,
p < 0.05; **, p < 0.01; ***,
p < 0.005 versus control.
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Fig. 4.
Effect of LPS treatment on RXR
(A), RXR
(B), and RXR
(C) gene transcription rates in hamster
liver. Syrian hamsters were injected IP with either saline or LPS
(100 µg of LPS/100 g of BW). Four hours later, livers were removed,
and nuclei for in vitro transcription were prepared as
described under "Experimental Procedures." Data (means ± S.E., n = 5) are expressed as a percentage of controls.
***, p < 0.005 versus control.
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Because cytokines, such as TNF and IL-1, mediate many of the changes
induced by LPS administration, we next examined the effect of TNF
and/or IL-1 on RXR mRNA levels. As shown in Fig. 3B,
2 h after the administration of TNF, IL-1, or TNF plus IL-1, there was a 63, 60, and 80% reduction in RXR mRNA levels,
respectively. Thus, the combination of TNF and IL-1 can reproduce the
effects of LPS.
Both RXR and RXR are also present in the liver but are expressed
at lower levels than RXR . As shown in Fig. 1, B and
C, LPS treatment (100 µg/100 g of BW) resulted in a
decrease in RXR and RXR protein levels in the liver of Syrian
hamsters. RXR was decreased by 61% as early as 2 h after LPS
administration but returned to normal by 8 h (Fig. 1C).
RXR protein levels also rapidly decreased following LPS treatment,
but in contrast to RXR , this decrease was sustained for at least
16 h (Fig. 1B). The decrease in protein levels of
RXR and RXR induced by LPS was a sensitive response, with the
half-maximal effect seen at less than 1 µg of LPS/100 g of BW for
RXR (Fig. 2C) and approximately 1 µg of LPS/100 g of BW
for RXR (Fig. 2B). Thus, LPS treatment not only decreases
RXR protein levels but also decreases the levels of RXR and
RXR , which are less abundant isoforms of RXR.
To determine whether the decreases in RXR and RXR could be due to
changes in mRNA levels, we next measured hepatic mRNA levels in
the liver following LPS treatment. At 4 h after LPS treatment,
there was a 76 and 90% reduction in the hepatic mRNA levels of
RXR and RXR , respectively (Fig. 3A). In contrast to RXR , the decreases in RXR and RXR mRNA levels were not
associated with a decrease in transcription (Fig. 4, B and
C).
We next examined the effect of TNF and/or IL-1 on RXR and RXR
mRNA levels in the liver. As shown in Fig. 3B, cytokine
treatment reduced RXR and RXR mRNA levels by approximately
50%. In contrast to the effect of cytokines on RXR mRNA levels,
cytokine administration did not reduce RXR or RXR mRNA levels
to the degree seen following LPS treatment.
LPS Treatment Also Reduces LXR and PPAR Expression in
Liver--
To determine whether the decrease in RXR expression is
associated with an alteration in LXR and PPAR expression, LXR and PPAR mRNA levels were measured in hamster liver following LPS treatment. LXR is abundantly expressed in liver and in tissues playing an important role in lipid metabolism (39), whereas LXR , which is also
present in the liver, displays a more widespread pattern of expression
(40). PPAR has been shown to be the major isoform in human (39), rat
(41), and mouse (42) liver. PPAR and PPAR are present in the
liver but at a lower level of expression than PPAR (39, 41, 42).
Four hours after LPS administration, there was an 89% reduction in
mRNA levels of LXR and PPAR (Fig. 5, A and B,
respectively). The level of expression of the minor isoforms was
reduced by 84% in the case of PPAR (Fig. 5B) and was not
significantly altered in the case of PPAR (Fig. 5B) and LXR (Fig. 5A). Thus, in contrast to the overall
inhibition of RXR species, LPS treatment lead to the specific
inhibition of LXR , PPAR , and PPAR but not LXR or
PPAR .

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Fig. 5.
Effect of LPS treatment on LXR
(A) and PPAR (B) mRNA levels in
hamster liver. Syrian hamsters were injected IP with either saline
or LPS (100 µg of LPS/100 g of BW). Four hours later, livers were
removed, and poly(A)+ RNA and Northern blots were prepared as described
under "Experimental Procedures." Data (means ± S.E.,
n = 5) are expressed as a percentage of controls. ***,
p < 0.005 versus control.
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LPS Administration Decreases the Binding of RXR Homodimers and
RXR·PPAR and RXR·LXR Heterodimers to Specific Response
Elements--
Electrophoretic gel mobility assays were carried out to
determine whether the decrease in RXR expression resulted in a decline in RXR binding to DNA. Nuclear hormone receptors recognize derivatives of a direct hexanucleotide repeat. The orientation of the half-sites and the number of nucleotides spacing the two half-sites determine the
specificity of the response element (3, 5). We used a
32P-labeled DNA oligonucleotide containing the RXR response
element, a direct repeat spaced by one nucleotide (DR1), from the
retinol-binding protein type II (CRBPII) promoter, which
preferentially binds to RXR homodimers (37). As shown in Fig.
6A, three major RXR complexes
were observed in the control samples. Competition with a 100-fold molar
excess of specific oligonucleotide, but not of mutated oligonucleotide,
demonstrated the specificity of the three complexes. In addition, a
portion of these complexes was supershifted after incubation of control
nuclear extract with anti-RXR and anti-RXR antibodies (Fig.
6C). Specifically, incubation with RXR antisera markedly
decreased the higher molecular weight complex, suggesting that this
complex is mainly composed of RXR homodimers. In our hands, RXR
antiserum was unable to supershift any of the three complexes. The
formation of RXR-DNA complexes was not affected by nonspecific IgG. At
4 h, LPS treatment induced an overall 74% (p < 0.005) decrease in RXR homodimer binding, with the two higher molecular
weight complexes being the most affected (Fig. 6, A and
B). Thus, the decrease in RXR nuclear protein levels is
associated with a decline in RXR binding activity during
endotoxemia.

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Fig. 6.
Effect of LPS treatment on RXR, PPAR, and LXR
binding to their specific response element. Syrian hamsters were
injected IP with either saline or LPS (100 µg of LPS/100 g of BW).
Four hours later, hepatic nuclear extracts were prepared as described
under "Experimental Procedures." Ten micrograms of nuclear extracts
were incubated with radiolabeled oligonucleotides representing binding
sites for RXR homodimers, and RXR·PPAR and RXR·LXR heterodimers.
A, representative electrophoretic gel mobility shift assays.
Unlabeled specific (100Xwt) and nonspecific
(100Xmut) competing oligonucleotides were included at
100-fold excess 1 h prior to the addition of the labeled probes.
Arrows represent specific bound complexes. B,
densitometric analysis of hepatic DNA-binding proteins. Data
(means ± S.E., n = 5) are expressed as a
percentage of controls. *, p < 0.05; ***,
p < 0.005 versus control. C,
electrophoretic mobility shift assay using a nuclear extract from a
control hamster performed in the presence of antibodies raised against
RXR (lane 2), RXR (lane 3), RXR
(lane 4), and rabbit IgG (lane 5). SS1
and SS2 represent the complexes supershifted by the RXR
and RXR antibodies, respectively.
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Because RXR is the obligatory partner for high affinity binding of PPAR
and LXR to their response elements, we next carried out electrophoretic
gel mobility assays to determine whether the down-regulation in RXR
species along with PPAR and LXR was associated with a decrease in
PPAR and/or LXR binding activity. The following oligonucleotides were
used: PPAR response element (DR1), derived from the PPAR response
element present in the acyl-CoA oxidase promoter; and CYP7-LXR response
element (DR4), derived from the LXR response element of the
CYP7A gene. As shown in Fig. 6, A and
B, 4 h after LPS administration, RXR·PPAR and
RXR·LXR binding were reduced by 90% (p < 0.005) and
58% (p < 0.05) compared with control, respectively.
Therefore, LPS treatment leads to a global decrease in RXR, PPAR, and
LXR dimer binding activity in the liver.
To determine whether the decrease in RXR·PPAR binding that we found
in hepatic nuclear extracts from LPS treated animals could be
associated with a decreased expression of a PPAR regulated gene, we
next examined the effect of LPS on ACS mRNA level in hamsters
pretreated with a specific PPAR agonist, Wy-14,643 (43). As reported
previously (21), LPS treatment alone resulted in a marked decrease
(72%) in ACS mRNA levels in liver at 4 h (Fig. 7). Five days of treatment with Wy-14,643
markedly up-regulated (2-fold) ACS mRNA levels, as expected (11,
44). Most importantly, LPS administration led to a marked reduction in
ACS mRNA levels in hamsters pretreated with Wy-14,643, indicating
that LPS, possibly by decreasing RXR·PPAR heterodimer binding, can
block the stimulatory effect of PPAR activators in liver.

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Fig. 7.
LPS effect on the expression of
ACS, a PPAR target gene,
after activation by a specific PPAR
agonist. Hepatic total RNAs were prepared 4 h after
saline or LPS administration (100 µg/100 g of BW) from hamsters
pretreated with saline or Wy-14,643 (5 mg/100 g of BW) for 5 days.
Northern blots were prepared as described under "Experimental
Procedures." Data (means ± S.E., n = 4-5) are
expressed as a percentage of controls after normalization to individual
18 S data. **, p < 0.01 versus
control.
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DISCUSSION |
Infection, inflammation, and trauma induce a wide array of
metabolic changes in the liver that constitute the APR (45). The APR is
mediated by cytokines, particularly TNF, IL-1, and IL-6 (46, 47). The
hepatic synthesis of certain proteins, such as C-reactive protein and
serum amyloid A, is increased (positive acute phase proteins), whereas
the synthesis of other proteins, such as albumin and transferrin, is
inhibited (negative acute phase proteins) (45).
The mechanism by which gene transcription is stimulated during the APR
has been extensively studied. Class I acute phase proteins (APPs) are
stimulated by IL-1 type cytokines, whereas class II APPs are stimulated
by the IL-6 family of cytokines (46, 47). IL-1-induced activation of
CEBP and NF B is thought to mediate the increase in transcription of
class I APP genes, whereas activation of CEBP and members of the STAT
family of transcription factors is thought to mediate the IL-6-induced
stimulation of class II APP gene expression (46, 47).
Much less is known about the molecular mechanisms responsible for the
repression of negative APPs. Down-regulation of specific hepatic
nuclear factors, such as HNF-1 and HNF-4, during APR (48) has been
implicated in the regulation of certain negative APPs. For example, a
decrease in HNF-1 is thought to be responsible for the reduced
transcription of albumin (49), the microsomal triglyceride transfer
protein (50) and the sodium-dependent bile acid transporter
(51), whereas a decrease in HNF-4 could account for the decline in
apoCIII levels (52, 53).
In the present paper, we demonstrate that the induction of the APR by
either LPS or cytokine administration decreases the levels of all three
RXR isoforms in the liver. The decrease in RXR , RXR , and RXR
protein levels occurs rapidly, within 2-4 h, and is sustained for as
long as 16 h for the most abundant isoform of RXR and also for
RXR . Moreover, this decrease in RXR protein levels is induced by low
doses of LPS (half-maximal effect occurring at approximately 1-2 µg
of LPS/100 g of BW, compared with a LD50 of approximately 5 mg/100 g of BW), indicating that this reduction in RXR is a very
sensitive response to LPS. The decrease in RXR protein levels is
accompanied by a marked reduction in RXR mRNA levels, suggesting
that a decrease in protein synthesis account for the reduction in
protein levels.
Interestingly, the decrease in RXR mRNA levels does not appear to
be entirely due to a decrease in RXR gene transcription. Nuclear run-on
assays did not demonstrate a change in RXR and RXR transcription and showed only a very modest 38%
decrease in RXR transcription, which is not sufficient to
account for the marked reduction in RXR mRNA levels following
LPS administration. It therefore appears that the decrease in RXR
mRNA levels is primarily due to an LPS-induced specific degradation
of RXR mRNA. Recent studies have suggested that LPS also reduces
connexin 32 mRNA levels in the liver by increasing their
degradation rate (54). Unfortunately, using in vivo models
such as these, it is difficult to carry out studies to directly
demonstrate that LPS accelerates RXR mRNA degradation. In addition
to the usual difficulties of measuring RNA degradation in
vivo, degradation studies typically use actinomycin D, and it
should be recognized that this compound dramatically increases the
sensitivity to LPS (55), which will make interpretation of the results
difficult. Definitive studies of the mechanism by which RXR mRNA
levels are decreased during the APR await the development of an
in vitro model.
The decrease in RXR protein levels in the liver during the APR may
affect the transcription of a variety of genes. In the present study,
we demonstrate that RXR binding to RXR·RXR response element is
decreased following LPS treatment. In addition to forming homodimers,
RXR is an obligate partner in heterodimers formed with several nuclear
hormone receptors, such as PPAR and LXR. We further demonstrate that
the expression of LXR , PPAR , and PPAR , along with the binding
of nuclear extracts from acute phase liver to RXR·PPAR (DR-1) and
RXR·LXR (DR-4) regulatory elements, is reduced. Because LPS treatment
did not significantly modify the level of expression of LXR and
PPAR , it would be of interest to determine whether the expression
and/or the binding of other nuclear hormone receptors, such as RAR,
thyroid hormone receptor, vitamin D receptor, and farnesoid X receptor,
that also form heterodimers with RXR, is also reduced.
Given the variety of nuclear hormone receptors that form obligate
heterodimers with RXR and the large number of genes that they regulate,
a decrease in RXR and some of its partners in the liver during the APR
could provide a mechanism to coordinately decrease the expression of a
large number of different proteins. Looking at one model gene,
ACS, which is regulated by PPAR (11), we demonstrate that
LPS administration decreases ACS mRNA levels not only in normal
animals, but also in animals in which ACS expression was induced by
prior treatment with the PPAR ligand, Wy-14,643. These data suggest
that induction of the APR can inhibit the stimulation of transcription
induced by PPAR activators. However, to understand the relative
importance of RXR repression and LXR or PPAR repression for the
decreases in gene transcription that occur during the APR, one will
have to develop transgenic models in which RXR levels are maintained
during the APR.
The APR results in marked alterations in lipid metabolism in the liver
(9). Whereas hepatic fatty acid uptake is increased and fatty acids are
preferentially esterified to form triglycerides, there is a concomitant
decrease in fatty acid oxidation and in bile acid synthesis. Many of
the enzymes and transporters involved in these metabolic changes, such
as carnitine palmitoyltransferase I, 3-hydroxy-3-methylglutaryl-CoA
synthase, acyl-CoA oxidase, ACS, FA transport protein, FA-binding
protein, and CYP7A are known to be regulated by PPAR or LXR (10-19).
It is possible that during the APR, the reduced availability of RXR
protein and possibly of other nuclear hormone receptors represents a
mechanism to coordinately regulate these metabolic changes in liver.
Additionally, it has recently been recognized that orphan receptors PXR
and CAR form heterodimers with RXR and modulate drug metabolism by
regulating the expression of CYP2 and CYP3 P450 enzymes (56). A
decrease in RXR could by itself explain the well characterized decrease in P450 enzymes and inhibition of drug metabolism that occurs during
the APR (57). Lastly, one would anticipate that genes regulated by
other nuclear hormone receptors that form heterodimers with RXR might
also be down-regulated during the APR. In fact, prior studies have
shown that the expression of the malic enzyme, which is regulated by
PPAR (58) and thyroid hormone receptor (59), is decreased after liver
injury (60), supporting this hypothesis.
In summary, the present manuscript demonstrates that the APR is
associated with a decrease in mRNAs coding for RXR proteins, resulting in a marked reduction in RXR protein levels in the liver. This reduction in RXR species appears to be primarily due to an increase in RNA degradation rate. RXR repression is associated with
reduced LXR and PPAR expression levels, resulting in an overall
decreased binding activity to regulatory elements that recognize
RXR·RXR, RXR·PPAR, and RXR·LXR dimers in nuclear extracts from
acute phase liver. It can be hypothesized that the reduction in RXR
levels, along with levels of other nuclear hormone receptors in the
liver, could be a mechanism to coordinately down-regulate the
expression of a large number of genes during the APR.
 |
ACKNOWLEDGEMENTS |
We thank Drs. David J. Mangelsdorf and Johan
Auwerx for their valuable suggestions.
 |
FOOTNOTES |
*
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.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.
To whom correspondence should be addressed: Dept. of Veterans
Affairs Medical Center, Metabolism Section (111F), 4150 Clement St.,
San Francisco, CA 94121. Tel.: 415-750-2005; Fax: 415-750-6927; E-mail: kfngld@itsa.ucsf.edu.
Published, JBC Papers in Press, March 21, 2000, DOI 10.1074/jbc.M000953200
 |
ABBREVIATIONS |
The abbreviations used are:
RXR, retinoid X
receptor;
PPAR, peroxisome proliferator-activated receptor;
LXR, liver
X receptor;
APR, acute phase response;
FA, fatty acid;
TNF, tumor
necrosis factor;
IL, interleukin;
LPS, lipopolysaccharide;
ACS, acyl-CoA synthetase;
BW, body weight;
IP, intraperitoneally;
APP, acute
phase protein;
mut, mutant;
HNF, hepatocyte nuclear factor.
 |
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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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T. L. Zimmerman, S. Thevananther, R. Ghose, A. R. Burns, and S. J. Karpen
Nuclear Export of Retinoid X Receptor {alpha} in Response to Interleukin-1beta-mediated Cell Signaling: ROLES FOR JNK AND SER260
J. Biol. Chem.,
June 2, 2006;
281(22):
15434 - 15440.
[Abstract]
[Full Text]
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T. R. Sweeney, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold
Decreased nuclear hormone receptor expression in the livers of mice in late pregnancy
Am J Physiol Endocrinol Metab,
June 1, 2006;
290(6):
E1313 - E1320.
[Abstract]
[Full Text]
[PDF]
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J Kwakkel, W M Wiersinga, and A Boelen
Differential involvement of nuclear factor-{kappa}B and activator protein-1 pathways in the interleukin-1{beta}-mediated decrease of deiodinase type 1 and thyroid hormone receptor {beta}1 mRNA.
J. Endocrinol.,
April 1, 2006;
189(1):
37 - 44.
[Abstract]
[Full Text]
[PDF]
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T. A. Richardson, M. Sherman, L. Antonovic, S. S. Kardar, H. W. Strobel, D. Kalman, and E. T. Morgan
HEPATIC AND RENAL CYTOCHROME P450 GENE REGULATION DURING CITROBACTER RODENTIUM INFECTION IN WILD-TYPE AND TOLL-LIKE RECEPTOR 4 MUTANT MICE
Drug Metab. Dispos.,
March 1, 2006;
34(3):
354 - 360.
[Abstract]
[Full Text]
[PDF]
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Y. Wang, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold
Downregulation of liver X receptor-{alpha} in mouse kidney and HK-2 proximal tubular cells by LPS and cytokines
J. Lipid Res.,
November 1, 2005;
46(11):
2377 - 2387.
[Abstract]
[Full Text]
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G. Zollner, M. Wagner, P. Fickert, A. Geier, A. Fuchsbichler, D. Silbert, J. Gumhold, K. Zatloukal, A. Kaser, H. Tilg, et al.
Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver
Am J Physiol Gastrointest Liver Physiol,
November 1, 2005;
289(5):
G798 - G805.
[Abstract]
[Full Text]
[PDF]
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A. Geier, C. G. Dietrich, S. Voigt, M. Ananthanarayanan, F. Lammert, A. Schmitz, M. Trauner, H. E. Wasmuth, D. Boraschi, N. Balasubramaniyan, et al.
Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver
Am J Physiol Gastrointest Liver Physiol,
November 1, 2005;
289(5):
G831 - G841.
[Abstract]
[Full Text]
[PDF]
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M. S. Kim, J. K. Shigenaga, A. H. Moser, K. R. Feingold, and C. Grunfeld
Suppression of estrogen-related receptor {alpha} and medium-chain acyl-coenzyme A dehydrogenase in the acute-phase response
J. Lipid Res.,
October 1, 2005;
46(10):
2282 - 2288.
[Abstract]
[Full Text]
[PDF]
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M. Kojima, K. Sekikawa, K. Nemoto, and M. Degawa
Tumor Necrosis Factor-{alpha}-Independent Downregulation of Hepatic Cholesterol 7{alpha}-Hydroxylase Gene in Mice Treated with Lead Nitrate
Toxicol. Sci.,
October 1, 2005;
87(2):
537 - 542.
[Abstract]
[Full Text]
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T. A. Richardson and E. T. Morgan
Hepatic Cytochrome P450 Gene Regulation during Endotoxin-Induced Inflammation in Nuclear Receptor Knockout Mice
J. Pharmacol. Exp. Ther.,
August 1, 2005;
314(2):
703 - 709.
[Abstract]
[Full Text]
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A. Jahan and J. Y. L. Chiang
Cytokine regulation of human sterol 12{alpha}-hydroxylase (CYP8B1) gene
Am J Physiol Gastrointest Liver Physiol,
April 1, 2005;
288(4):
G685 - G695.
[Abstract]
[Full Text]
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S. Teng and M. Piquette-Miller
The Involvement of the Pregnane X Receptor in Hepatic Gene Regulation during Inflammation in Mice
J. Pharmacol. Exp. Ther.,
February 1, 2005;
312(2):
841 - 848.
[Abstract]
[Full Text]
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X. Deng, M. B. Elam, H. G. Wilcox, L. M. Cagen, E. A. Park, R. Raghow, D. Patel, P. Kumar, A. Sheybani, and J. C. Russell
Dietary Olive Oil and Menhaden Oil Mitigate Induction of Lipogenesis in Hyperinsulinemic Corpulent JCR:LA-cp Rats: Microarray Analysis of Lipid-Related Gene Expression
Endocrinology,
December 1, 2004;
145(12):
5847 - 5861.
[Abstract]
[Full Text]
[PDF]
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M. S. Kim, J. Shigenaga, A. Moser, C. Grunfeld, and K. R. Feingold
Suppression of DHEA sulfotransferase (Sult2A1) during the acute-phase response
Am J Physiol Endocrinol Metab,
October 1, 2004;
287(4):
E731 - E738.
[Abstract]
[Full Text]
[PDF]
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M. You and D. W. Crabb
Recent Advances in Alcoholic Liver Disease II. Minireview: molecular mechanisms of alcoholic fatty liver
Am J Physiol Gastrointest Liver Physiol,
July 1, 2004;
287(1):
G1 - G6.
[Abstract]
[Full Text]
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W. Khovidhunkit, M.-S. Kim, R. A. Memon, J. K. Shigenaga, A. H. Moser, K. R. Feingold, and C. Grunfeld
Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host
J. Lipid Res.,
July 1, 2004;
45(7):
1169 - 1196.
[Abstract]
[Full Text]
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K. Feingold, M. S. Kim, J. Shigenaga, A. Moser, and C. Grunfeld
Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response
Am J Physiol Endocrinol Metab,
February 1, 2004;
286(2):
E201 - E207.
[Abstract]
[Full Text]
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C. Handschin and U. A. Meyer
Induction of Drug Metabolism: The Role of Nuclear Receptors
Pharmacol. Rev.,
December 1, 2003;
55(4):
649 - 673.
[Abstract]
[Full Text]
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W. Khovidhunkit, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold
Endotoxin down-regulates ABCG5 and ABCG8 in mouse liver and ABCA1 and ABCG1 in J774 murine macrophages: differential role of LXR
J. Lipid Res.,
September 1, 2003;
44(9):
1728 - 1736.
[Abstract]
[Full Text]
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M. Fischer, M. You, M. Matsumoto, and D. W. Crabb
Peroxisome Proliferator-activated Receptor {alpha} (PPAR{alpha}) Agonist Treatment Reverses PPAR{alpha} Dysfunction and Abnormalities in Hepatic Lipid Metabolism in Ethanol-fed Mice
J. Biol. Chem.,
July 18, 2003;
278(30):
27997 - 28004.
[Abstract]
[Full Text]
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H. Ishii, T. Tezuka, H. Ishikawa, K. Takada, K. Oida, and S. Horie
Oxidized phospholipids in oxidized low-density lipoprotein down-regulate thrombomodulin transcription in vascular endothelial cells through a decrease in the binding of RAR{beta}-RXR{alpha} heterodimers and Sp1 and Sp3 to their binding sequences in the TM promoter
Blood,
June 15, 2003;
101(12):
4765 - 4774.
[Abstract]
[Full Text]
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M. Trauner and J. L. Boyer
Bile Salt Transporters: Molecular Characterization, Function, and Regulation
Physiol Rev,
April 1, 2003;
83(2):
633 - 671.
[Abstract]
[Full Text]
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M. S. Kim, J. Shigenaga, A. Moser, K. Feingold, and C. Grunfeld
Repression of Farnesoid X Receptor during the Acute Phase Response
J. Biol. Chem.,
March 7, 2003;
278(11):
8988 - 8995.
[Abstract]
[Full Text]
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M. Jalouli, L. Carlsson, C. Ameen, D. Linden, A. Ljungberg, L. Michalik, S. Eden, W. Wahli, and J. Oscarsson
Sex Difference in Hepatic Peroxisome Proliferator-Activated Receptor {alpha} Expression: Influence of Pituitary and Gonadal Hormones
Endocrinology,
January 1, 2003;
144(1):
101 - 109.
[Abstract]
[Full Text]
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A. P. Beigneux, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold
Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver
Am J Physiol Endocrinol Metab,
January 1, 2003;
284(1):
E228 - E236.
[Abstract]
[Full Text]
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C. Blanquart, O. Barbier, J.-C. Fruchart, B. Staels, and C. Glineur
Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) Turnover by the Ubiquitin-Proteasome System Controls the Ligand-induced Expression Level of Its Target Genes
J. Biol. Chem.,
September 27, 2002;
277(40):
37254 - 37259.
[Abstract]
[Full Text]
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R. Kaplan, X. Gan, J. G. Menke, S. D. Wright, and T.-Q. Cai
Bacterial lipopolysaccharide induces expression of ABCA1 but not ABCG1 via an LXR-independent pathway
J. Lipid Res.,
June 1, 2002;
43(6):
952 - 959.
[Abstract]
[Full Text]
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I. Pineda Torra, Y. Jamshidi, D. M. Flavell, J.-C. Fruchart, and B. Staels
Characterization of the Human PPAR{alpha} Promoter: Identification of a Functional Nuclear Receptor Response Element
Mol. Endocrinol.,
May 1, 2002;
16(5):
1013 - 1028.
[Abstract]
[Full Text]
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J. Bjorkegren, A. Beigneux, M. O. Bergo, J. J. Maher, and S. G. Young
Blocking the Secretion of Hepatic Very Low Density Lipoproteins Renders the Liver More Susceptible to Toxin-induced Injury
J. Biol. Chem.,
February 8, 2002;
277(7):
5476 - 5483.
[Abstract]
[Full Text]
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R. A. Memon, A. H. Moser, J. K. Shigenaga, C. Grunfeld, and K. R. Feingold
In Vivo and in Vitro Regulation of Sterol 27-Hydroxylase in the Liver during the Acute Phase Response. POTENTIAL ROLE OF HEPATOCYTE NUCLEAR FACTOR-1
J. Biol. Chem.,
August 3, 2001;
276(32):
30118 - 30126.
[Abstract]
[Full Text]
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G. Zollner, P. Fickert, D. Silbert, A. Fuchsbichler, C. Stumptner, K. Zatloukal, H. Denk, and M. Trauner
Induction of short heterodimer partner 1 precedes downregulation of Ntcp in bile duct-ligated mice
Am J Physiol Gastrointest Liver Physiol,
January 1, 2002;
282(1):
G184 - G191.
[Abstract]
[Full Text]
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M. J. Evans, A. Eckert, K. Lai, S. J. Adelman, and D. C. Harnish
Reciprocal Antagonism Between Estrogen Receptor and NF-{kappa}B Activity In Vivo
Circ. Res.,
October 26, 2001;
89(9):
823 - 830.
[Abstract]
[Full Text]
[PDF]
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Copyright © 2000 by the American Society for Biochemistry and Molecular Biology.
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