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(Received for publication, February
14, 1996) From the
The yeast two-hybrid system was used to isolate novel cellular
factors that interact with the mouse peroxisome proliferator-activated
receptor
Peroxisome proliferator-activated receptors (PPARs) ( PPARs activate expression of target genes by recognizing peroxisome
proliferator response elements (PPREs) composed of TGACCT-related
direct repeats that are spaced by one nucleotide
(DR1)(11, 12) . Specific DNA binding is manifested
through heterodimerization with the 9-cis-retinoic acid
receptor, RXR
Figure 1:
LXR
Figure 2:
LXR
Figure 3:
LXR
Control transfections
demonstrated that LXR In summary, we have shown that PPAR
Volume 271,
Number 16,
Issue of April 19, 1996 pp. 9189-9192
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
Interacts with the Peroxisome
Proliferator-activated Receptor and Inhibits Peroxisome Proliferator
Signaling (*)
(PPAR). One of the interacting clones isolated
encoded LXR, a recently described human orphan nuclear hormone
receptor. LXR bound directly to PPAR, as well as to the
common heterodimerization partner 9-cis-retinoic acid receptor
(RXR). LXR did not form a DNA binding complex with PPAR
on synthetic hormone response elements composed of direct repeats of
the TGACCT consensus half-site or on naturally occurring peroxisome
proliferator response elements (PPREs) or LXR response elements.
However, LXR inhibited binding of PPAR/RXR heterodimers
to PPREs, and coexpression of LXR in mammalian cells antagonized
peroxisome proliferator signaling mediated by PPAR/RXR in
vivo. These findings identify a novel partner for PPAR and
suggest that LXR plays a role in modulating PPAR-signaling
pathways in the cell.
)are recently described members of the ligand-activated
nuclear hormone receptor superfamily, which includes receptors for
steroids, vitamin D, and thyroid and retinoid hormones(1) .
PPARs have been shown to regulate a broad spectrum of genes involved in
lipid metabolism, cellular growth, and differentiation(2) .
Consequently, there is a great deal of interest in understanding their
specificity and mechanisms of action. PPARs were originally identified
as factors that mediate transcriptional responses to peroxisome
proliferators, a broad class of xenobiotic chemicals that include
fibrate hypolipidemic drugs and other nongenotoxic rodent
hepatocarcinogens(3, 4) . Subsequently, PPARs were
shown to be differentially activated by a variety of long chain fatty
acids and lipid-like compounds(5) , suggesting that fatty acids
or fatty acid derivatives serve as physiological activators. PPARs
exist in a variety of pharmacologically distinct subtypes and isoforms
that are differentially expressed and which mediate distinct patterns
of tissue-specific gene
expression(4, 6, 7, 8) . For
example, mouse (m) PPAR
triggers adipogenesis in cultured cells (8) and is selectively activated by
15-deoxy-
-prostaglandin J2, a recently identified
high affinity ligand of this PPAR subtype(9, 10) . (13, 14) , another member of the
nuclear hormone receptor superfamily that also serves as a
heterodimerization partner for thyroid hormone, retinoic acid, and
vitamin D receptors(1) . The involvement of PPARs in multiple
and diverse cellular functions suggests that these receptors may be
integrated with other cellular signaling pathways, in addition to the
well characterized RXR pathway. Indeed, the reciprocal modulation
of thyroid hormone and peroxisome proliferator-responsive genes through
cross-talk between thyroid hormone receptors and PPARs has recently
been demonstrated(15, 16, 17) . Moreover, it
has been reported that rat PPAR heterodimerizes with the thyroid
hormone receptor(18) , although this conclusion remains
controversial(15) . Unraveling the pleiotropic functions of
PPARs requires identification of the full spectrum of factors that
interact with PPARs. In this report, we used the yeast two-hybrid
system (19) to isolate novel factors that interact with
mPPAR. One mPPAR-interacting factor isolated was identified
as LXR, a recently described human orphan nuclear hormone receptor
that appears to be involved in a novel retinoid signaling
pathway(20) . LXR inhibited the binding of
mPPAR/RXR to PPREs in vitro and antagonized
transcriptional activation by mPPAR in vivo. Our findings
demonstrate that nuclear receptors other than RXR bind directly to
PPAR and may play a role in modulating the cellular functions of
this receptor.
Two-hybrid Library Screening
Yeast two-hybrid
vectors expressing full-length human RXR and mPPAR as fusions
to the GAL4 DNA-binding domain (GBD-RXR and GBD-mPPAR,
respectively) and RXR fused to the GAL4 activation domain
(GAD-RXR) have been described (21) . GBD-mPPAR was not
suitable for two-hybrid library screening, since it induced a low level
of constitutive activity of the 
-galactosidase reporter gene when
expressed alone in yeast(21) . We therefore constructed a
modified vector, GBD-NmPPAR (missing the amino-terminal 83 amino
acid codons of mPPAR) that was devoid of this intrinsic activation
function but remained capable of interacting with RXR (see Table 1). This derivative was used as bait in the two-hybrid
system. Saccharomyces cerevisiae strain HF7c (MATa, ura3-52, his3-200, lys2-801, ade2-101, trp1-901, leu2-3, 112, gal4- 542, gal80-538, LYS::GAL1
-GAL1
-HIS3, URA3::GAL4
CyC1-lacZ)
harboring GBD-NmPPAR was subjected to electroporation (22) with a HeLa cell cDNA library constructed in the GAD
vector pGADGH (Clontech). Transformants were plated onto synthetic
complete media plates lacking histidine, leucine, and tryptophan and
containing 25 mM 3-amino-1,2,4-triazole. His
,
leu, trp colonies were assayed for
expression of the -galactosidase reporter gene by agarose overlay
assay using 0.2% (v/v) Triton X-100 as a permeabilization agent.
Library plasmids were rescued by electroporation into Escherichia
coli ElectroMAX DH10B (Life Technologies, Inc.), and isolated
plasmids were used to retransform S. cerevisiae HF7c.
Candidate clones were tested for interaction against GBD-NmPPAR
and to GBD-RXR and also to irrelevant fusion proteins and the
empty fusion vector so as to eliminate false positives (23) and
to ensure that the his and -galactosidase
phenotypes were dependent on the presence of both the respective
GAD-cDNA library vectors and GBD-NmPPAR. Positive clones were
recovered and subjected to partial 5`- and 3`-sequence analysis. Two
clones contained the same partial cDNA that encoded a novel member of
the nuclear hormone receptor superfamily, subsequently shown to be
nearly identical to the recently described human LXR (20) . One of these clones (GAD-SM1; encoding amino acid
residues 61-447 of LXR) was selected for further analysis.
The remaining positive clones were not related to LXR or to other
nuclear receptors and will be the focus of future studies.
Cloning a Full-length LXR
The
1.2-kilobase pair (kbp) insert of GAD-SM1 was labeled with
[ cDNA-
P]dATP by random priming and used to
probe, under high stringency conditions, a 5`-stretch 
gt11 human
liver cDNA library (Stratagene). The largest hybridizing clone
contained a 1.7-kbp insert. The cDNA was sequenced in both directions
and shown to contain the entire 447-amino acid long open reading frame
corresponding to the published sequence of LXR(20) .In Vitro Transcription/Translation
In vitro expression vectors for mPPAR and human RXR have been
described (14) . The entire open reading frame of LXR was
amplified from the human liver cDNA library plasmid by the polymerase
chain reaction (forward primer,
5`-GCGCGGATCCGGTACCATGTCCTTGTGGCTGGGGGC; reverse primer,
5`-GCGCGGATCCGATATCTCATTCGTGCACATCCCAGATC; initiator codon is
underlined) and cloned into the BglII site of the SP6
transcription vector pSPUTK. Transcription of the different cDNAs,
followed by translation in rabbit reticulocytes, was performed using a
coupled system (Promega), as described previously (14, 24) .Protein Binding Assays
Maltose-binding protein
(MBP)-mPPAR and MBP-RXR fusion protein expression vectors
were constructed in pMAL-2c (New England Biolabs), and the fusion
proteins were purified by affinity chromatography according to the
manufacturer's instructions. Purified MBP-RXR,
MBP-mPPAR, and MBP proteins (2 mg/ml in column buffer (20 mM Tris-HCl (pH 7.4), 200 mM NaCl, 1 mM EDTA, 1
mM dithiothreitol, 20% (v/v) glycerol)) were adsorbed to
amylose resin (4.5 mg/ml settled resin) and resuspended as a 50% slurry
in column buffer. Twenty µl of slurry was adjusted to 500 µl
with column buffer containing 0.2% (v/v) Nonidet P-40 and 2% bovine
serum albumin (BSA) and incubated with 1-5 µl of programmed
reticulocyte lysate for 30 min at room temperature with continuous
mixing. Beads were washed sequentially with 20 volumes of column buffer
containing 0.2% (v/v) Nonidet P-40 and 2% BSA; column buffer containing
0.1% (v/v) Nonidet P-40 and 2% BSA; and column buffer alone. Bound
material was eluted from beads by boiling in SDS sample buffer and
analyzed by SDS-polyacrylamide gel electrophoresis.Gel Retardation Analysis
Electrophoretic mobility
shift assays were carried out as before(14, 24) .
Synthetic oligonucleotide probes corresponding to the rat fatty
acyl-CoA oxidase (AOx) and enoyl-CoA hydratase/3-hydroxyacyl-CoA
dehydrogenase (HD) PPREs have been described(14) . The
following double-stranded oligonucleotides containing TGACCT direct
repeats spaced by 0-5 nucleotides (DR0-DR5) were
synthesized (for each, only the top strand is shown; TGACCT direct
repeats are underlined; single-stranded BamHI compatible ends
are in lower case): DR0, gatcTTCTGACCTTGACCTGG; DR1,
gatcTTCTGACCTCTGACCTGG; DR2, gatcTTCTGACCTCCTGACCTGG; DR3,
gatcTTCTGACCTCCTTGACCTGG; DR4, gatcTTCTGACCTCCTGTGACCTGE; DR5,
gatcTTCTGACCTCCTGGTGACCTGG. The LXR response element (LXRE) (20) was synthesized by annealing
5`-GATCCTTGCGGTTCCCAGGGTTTAAATAAGTTCATCTA and the complementary strand
5`-GATCTAGATGAACTTATTTAAACCCTGGGAACCGCAAG.Transient Transfections and Measurement of Luciferase
Activity
mPPAR and RXR expression plasmids and the
AOx-PPRE luciferase reporter plasmid (pAOx(X2)luc) have been
described(14) . The mammalian expression vector for LXR
was constructed by cloning the LXR cDNA into pRc/CMV (Invitrogen).
Reporter plasmids containing two tandem copies of the synthetic DR4 or
DR1 direct repeat elements (pDR4(X2)luc and
pDR1(X2)luc, respectively) were constructed by cloning the
corresponding double-stranded oligonucleotides described above into the BglII site of the enhancerless SV40 promoter/luciferase
expression vector pGL2 (Promega). Transfection of BSC40 cells and
measurement of luciferase activity were carried out as described before (12, 14, 24) . Where indicated, the
peroxisome proliferator Wy-14,643 or the RXR ligand
9-cis-retinoic acid was added to final concentrations of
10
and 10
M,
respectively (from 100 
stocks in dimethyl sulfoxide). Control
cells were treated with vehicle alone.
Interaction Cloning of PPAR-interacting
Factors
Yeast harboring GBD-NmPPAR were used to screen
a HeLa cell cDNA library fused to the GAL4 transactivation domain. Of 5
10
independent transformants screened, 9 colonies
remained blue in color and his upon clonal
purification. Retransformation of rescued plasmids confirmed that all 9
candidate clones conferred the his and
-gal phenotypes only in the presence of
GBD-NmPPAR. Two positive clones, designated GAD-SM1 and GAD-KM1,
contained overlapping sequences of the same cDNA that partially encoded
a previously undescribed member of the nuclear hormone receptor
superfamily. Interestingly, the same clone was isolated in an
independent screen for RXR-interacting factors (data not
presented), demonstrating that this factor also interacts with RXR (Table 1). A 1.7-kbp cDNA was isolated from a gt11 human
liver cDNA library using GAD-SM1 as a probe and shown to contain an
open reading frame encoding a 447-amino acid polypeptide. After this
work was completed, Willy and co-workers (20) reported the
cloning of a cDNA encoding a novel orphan nuclear hormone receptor
using low stringency screening of a human liver cDNA library. The cDNA
for this receptor, designated LXR, is essentially identical at
both the nucleotide and deduced amino acid sequence level to the cDNA
clone isolated here by mPPAR interaction cloning. The only
differences noted in the deduced polypeptide are a phenylalanine in
place of the leucine at position 192 and a histidine in place of the
leucine at position 414. LXR was shown to interact with
RXR(20) , consistent with our two-hybrid analysis results.
By convention, we will refer to our mPPAR-interacting receptor as
LXR.LXR
To confirm that LXR Interacts with mPPAR and RXR in
Vitro physically interacts with
mPPAR and RXR, protein binding assays were carried out using
immobilized MBP fusion proteins and
[
S]methionine-labeled LXR synthesized in vitro. Labeled LXR bound to both MBP-mPPAR (Fig. 1a, lane 4) and MBP-RXR (Fig. 1b, lane 6) but not to the control MBP
beads (Fig. 1a, lane 2; Fig. 1b, lane 3). A labeled luciferase control
protein did not bind to beads complexed with MBP (Fig. 1, a and b, lanes 1), MBP-mPPAR (Fig. 1a, lane 3), or MBP-RXR (Fig. 1b, lane 4), demonstrating the specificity of the
observed interactions. Quantitative analysis indicated that LXR
bound approximately 10-fold more efficiently to RXR vis à vis mPPAR. LXR thus binds directly to
both mPPAR and RXR in vitro.
interacts with mPPAR and
RXR in vitro.
[S]Methionine-labeled LXR synthesized in vitro was incubated with immobilized MBP-mPPAR,
MBP-RXR, and MBP, as indicated. Bound radiolabeled protein was
analyzed by polyacrylamide gel electrophoresis. Labeled luciferase was
used as a negative control. NRIP1 in panel b is a
truncated version of LXR that is missing 60 amino-terminal amino
acids. This derivative retains the ability to interact with RXR (lane 5) and mPPAR (not
shown).
LXR
To identify
potential mPPAR Binds to Direct Repeat Hormone Response Elements
Cooperatively with RXR but Not with mPPAR/LXR DNA-binding sites, we synthesized a
series of oligonucleotides that contained TGACCT direct repeats
separated by 0-5 nucleotides (DR0-DR5) and tested them in
electrophoretic mobility shift assays with in vitro translated
LXR, RXR, and mPPAR alone or in combination. Binding
studies were also carried out with natural PPREs from the HD and AOx
genes and with a natural LXRE previously identified in the mouse
mammary tumor virus promoter(20) . As shown in Fig. 2a, mPPAR, LXR, and RXR on their
own did not bind to any of the elements tested. However, LXR bound
cooperatively with RXR to a DR4 element, the LXRE, and to a lesser
extent, to a DR5 element, as reported previously (20) . As
expected, mPPAR/RXR heterodimers bound preferentially to a
DR1 element as well as to the AOx- and HD-PPREs. In contrast,
cooperative binding of LXR and mPPAR was not observed on any
of these synthetic direct repeat or natural response elements. Whether
there exist natural and specific DNA target sites recognized by
mPPAR/LXR heterodimers remains to be determined.
binds cooperatively with RXR
but not with mPPAR to synthetic or natural response elements.
Electrophoretic mobility shift assays were carried out by incubating in vitro synthesized LXR, mPPAR, and RXR (1
µl of programmed reticulocyte lysate), as indicated, with synthetic
DR0-DR5 direct repeat response element, AOx-PPRE, HD-PPRE, or
LXRE probes (panel a). Panel b, the HD- and AOx-PPREs
were incubated with constant amounts of RXR and mPPAR (1
µl of programmed reticulocyte lysate each) and increasing amounts
of LXR (0.5-4 µl of programmed reticulocyte lysate).
Protein concentration in each reaction was normalized with unprogrammed
reticulocyte lysate as appropriate.
LXR
Coincubation of LXR Inhibits Binding of mPPAR/RXR
Heterodimers to PPREs with RXR and
mPPAR resulted in a decrease in the binding of mPPAR/RXR
to the HD- and AOx-PPREs (Fig. 2a, compare lanes 5 and 8). Similarly, mPPAR reduced binding of
LXR/RXR to DR4 and DR5 elements and to the LXRE (compare lanes 7 and 8). Coincubation with increasing amounts
of LXR resulted in a progressive decrease in the binding of
mPPAR/RXR heterodimers to the HD- and AOx-PPREs (Fig. 2b). Since LXR binds directly to mPPAR
and to RXR, this inhibition is likely the result of LXR
sequestering one, or both, of these receptors into non-binding
complexes. Reciprocally, mPPAR can competitively inhibit the
binding of LXR/RXR to the LXRE and to synthetic DR target
sites through the formation of both LXR/mPPAR and
mPPAR/RXR heterodimers.LXR
-To investigate the effect of LXR Antagonizes Peroxisome Proliferator-mediated
Signaling in Vivo on
peroxisome proliferator-mediated signaling in vivo, a
luciferase reporter plasmid containing the AOx-PPRE
(pAOx(X2)luc) was cotransfected along with LXR, RXR,
and mPPAR expression vectors into BSC40 cells, and luciferase
activity was monitored. LXR and mPPAR individually or in
combination had little effect on reporter gene expression either in the
presence or absence of the peroxisome proliferator Wy-14,643 (Fig. 3a) or the RXR ligand
9-cis-retinoic acid (not shown). However, LXR potently
inhibited induction mediated by mPPAR/RXR. As shown in Fig. 3b, cotransfection with increasing amounts of the
LXR expression plasmid led to a progressive reduction in
drug-independent and -dependent induction of the AOx-PPRE reporter gene
construct by mPPAR/RXR. The inclusion of
9-cis-retinoic acid in the transfections along with Wy-14,643
had little effect on LXR-mediated repression. Similar findings
were obtained using an HD-PPRE luciferase reporter gene construct (data
not presented). Thus, LXR antagonizes transactivation by
mPPAR/RXR in vivo.
antagonizes
mPPAR/RXR-mediated transcriptional activation by peroxisome
proliferators. Panel a, the pAOx(X2)luc reporter
plasmid was cotransfected into BSC40 cells with LXR, mPPAR,
and RXR expression plasmids (0.5 µg each) in the absence or
presence of the peroxisome proliferator Wy-14,643, as indicated, and
luciferase activity was measured. Panel b, effect of
increasing amounts of LXR expression vector in the presence of
constant amounts of mPPAR and RXR expression vectors, with
and without 9-cis-retinoic acid and Wy-14,643. Panel
c, activation of a DR4 reporter gene construct by
LXR/RXR. Transfections were carried out with LXR and
RXR expression plasmids and with luciferase reporter gene
constructs that contained a synthetic DR4 element
(pDR4(X2)luc) or a DR1 element (pDR1(X2)luc), as
indicated. Luciferase activity (±S.D.) in panels a and b is the average (corrected against the -galactosidase
internal reference) from three independent transfections, each carried
out in duplicate. The values shown were normalized to the value
obtained with cotransfected RXR and mPPAR expression plasmids
in the presence of Wy-14,643, which was taken as 100%. In panel
c, the values are from duplicate transfections (values did not
vary by more than 15%) and were normalized to the value obtained with
the respective reporter gene alone, which was taken as
1.
was functionally expressed under these
conditions. Thus, co-expression of LXR and RXR activated
expression of a reporter gene that contained a synthetic DR4
(pDR4(X2)luc) response element but not a DR1
(pDR1(X2)luc) response element (Fig. 3c).
Activation of the DR4 reporter gene by LXR/RXR was increased
in the presence of 9-cis-retinoic acid but was not dependent
upon its presence. Willy and co-workers (20) have also
demonstrated that LXR interacts with endogenous RXR to
mediate transcriptional activation through DR4 elements; however, under
these conditions, activation was observed only in the presence of
RXR-specific ligands. Our findings indicate that LXR also
activates transcription in the absence of RXR-specific ligands when
RXR is co-expressed. This is consistent with previous findings
that LXR homologs isolated from rat (RLD-1, rUR) and human (NER,
hUR) (25, 26, 27) also activate transcription
via DR4 target sites in the absence of added RXR-specific ligands. can interact directly with
other members of the nuclear hormone receptor superfamily in addition
to RXR, suggesting that combinatorial receptor interactions
involving PPARs are more extensive than previously anticipated.
Moreover, our findings indicate that both LXR and PPARs play a
broader physiological role in the convergence of distinct receptor
signaling pathways. Since LXR binds to the two identified
components that are necessary for peroxisome proliferator
responsiveness, there is potential for complex and diverse effects on
both retinoid and peroxisome proliferator signaling pathways. The
physiological importance of LXR and related receptors in PPAR
signaling is not known at present. Thus far, we have demonstrated that
LXR is a negative regulator of PPAR-mediated activation of
peroxisome proliferator-responsive genes. Whether PPAR/LXR
heterodimers may also positively regulate gene expression awaits the
definition of natural high affinity binding sites and the
identification of potential LXR ligands and target genes.
) response element; MBP, maltose-binding protein; PPRE,
peroxisome proliferator response element; RXR,
9-cis-retinoic acid receptor.
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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S. L. Marcus, C. J. Winrow, J. P. Capone, and R. A. Rachubinski A p56lck Ligand Serves as a Coactivator of an Orphan Nuclear Hormone Receptor J. Biol. Chem., November 1, 1996; 271(44): 27197 - 27200. [Abstract] [Full Text] [PDF]
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D. C. Jones, X. Ding, and R. A. Daynes Nuclear Receptor Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) Is Expressed in Resting Murine Lymphocytes. THE PPARalpha IN T AND B LYMPHOCYTES IS BOTH TRANSACTIVATION AND TRANSREPRESSION COMPETENT J. Biol. Chem., February 22, 2002; 277(9): 6838 - 6845. [Abstract] [Full Text] [PDF]
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