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Departments of Biological Chemistry and Medicine (H.R.K., C.M.N., B.A.L., P.A.E.), University of California, Los Angeles, California 90095; Laboratory of Metabolism (C.J.S., F.J.G.,) Division of Basic Sciences, National Institutes of Health, Bethesda, Maryland 20892; Molecular Biology Institute (K.R., P.A.E.), University of California, Los Angeles, California 90095; GlaxoSmithKline (S.A.J., T.M.W.) Nuclear Receptor Discovery Research, Research Triangle Park, North Carolina 27709
Address all correspondence and requests for reprints to: Peter A. Edwards, Ph.D., Department of Biological Chemistry, University of California, Los Angeles, California 90095. E-mail: pedwards{at}mednet.ucla.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The expression of the farnesoid X-activated receptor (FXR; NR1H4), a member of this superfamily, is restricted to the liver, kidney, intestine, and adrenal gland (4). The farnesoid X-activated receptor (FXR) heterodimerizes with RXR and binds to FXR response elements (FXREs) within the regulatory regions of target genes (4). The idealized FXRE, comprised of two hexanucleotide repeats (AGGTCA) arranged as inverted repeats with one nucleotide spacing between the two half-sites, is referred to as an IR-1 (4, 5).
Forman et al. (4) originally cloned rat FXR and reported that farnesol or juvenile hormone III weakly activated the FXR/RXR heterodimer. Independently, Seol et al. (6) cloned RIP-14, the murine homolog of rat FXR. Subsequent studies identified a nonphysiological synthetic retinoid, TTNPB, 4-[E-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl] benzoic acid, as a potent activator of both rat and murine FXR (7). In 1999, three laboratories made the important and unexpected observation that bile acids function as ligand activators for both rodent and human FXR (8, 9, 10). Chenodeoxycholate (CDCA) (8, 9, 10), a primary bile acid that is synthesized in the liver as a result of oxidation and catabolism of cholesterol, is the most potent ligand for FXR (11). At the present time, primary response genes that are known to be activated in an FXR- and CDCA-dependent manner are limited to the ileal bile acid-binding protein (8, 12), the phospholipid transfer protein (PLTP) (5, 13), and the small heterodimer partner (SHP), an unusual member of the nuclear receptor family which lacks a DNA-binding domain (14, 15). Recent studies demonstrate that SHP binds to and inactivates the liver receptor homolog 1, a transcription factor that is required for active transcription of the CYP7A1 gene (14, 15). Thus, increased expression of SHP, in response to activated FXR, results in a decrease in CYP7A1 transcription and bile acid synthesis (14).
In contrast, the physiological effects that result from induction of ileal bile acid-binding protein and PLTP by FXR remain unknown. Insights into other possible roles of FXR in lipid metabolism were recently reported by Maloney et al.; these authors identified a novel synthetic FXR ligand (GW4064) that, when administered to rats for 7 d, resulted in an approximate 50% decrease in plasma triglyceride levels (16). The mechanism by which GW4064 decreases plasma triglyceride levels is currently unknown. These findings, together with the recent observation that plasma triglyceride levels are increased 150% in FXR null mice, implicate FXR as a key regulator in the control of plasma lipids (17).
In the present study, suppression subtractive hybridization was used to identify apolipoprotein C-II (apoC-II) as a target of FXR in vivo and in vitro. To maximize the number of induced genes, we used HepG2 cells that stably overexpressed FXR, as a result of infection with a retrovirus that encodes FXR. Herein, we report that both apoC-II and PLTP are induced by FXR in isolated cells and in livers of mice fed diets supplemented with an FXR ligand. Induction of these genes in vivo correlates with decreased plasma triglyceride levels. Consequently, activation of FXR/RXR may provide an alternative approach in the clinical management of certain hyperlipidemias.
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RESULTS |
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, treatment of HepG2-vector cells with 100
µM CDCA results in a 5-fold increase in apoC-II mRNA
(compare lanes 1 and 2), presumably as a result of very low levels of
endogenous FXR in HepG2 cells. In contrast, the HepG2-FXR cells
expressed detectable levels of FXR mRNA (as the FXR-IRES-Neo
transcript) (Fig. 1B) and elevated basal levels of apoC-II mRNA (Fig. 1A, lane 3 vs. 1). Addition of 100
µM CDCA to the HepG2-FXR cells resulted in a
further increase in apoC-II mRNA to levels that are 15-fold greater
than in the DMSO-treated HepG2-vector cells (Fig. 1A, lanes 4
vs. 1).
Incubation of HepG2-FXR cells with 100 µM CDCA resulted
in induction of apoC-II mRNA as early as 12 h, and maximal levels
were attained after 48 h (Fig. 1B). Induction of apoC-II mRNA was
maximal at 100 µM CDCA (Fig. 1C). Although higher levels
of CDCA resulted in a decline in apoC-II mRNA levels, this effect
appears not to be due to toxicity as we have identified other mRNAs
from the SSH screen, such as the canalicular multispecific organic
anion transporter, that are maximally induced at 250 µM
CDCA (data not shown). Addition of TTNPB (5 µM) to
HepG2-FXR cells also resulted in increased apoC-II mRNA levels (Fig. 1C), consistent with the observation that this synthetic retinoid can
activate FXR (7).
FXR binds to FXREs as an FXR/RXR heterodimer (4, 5),
and RXR functions as a permissive heterodimer, as evidenced by
transactivation of reporter genes by ligands for either RXR or FXR
(18). Consistent with this model, apoC-II mRNA levels
increased when HepG2-FXR cells were treated with either a synthetic
RXR-specific ligand (LG100153) or the FXR ligand, CDCA (Fig.
1D). Addition of both LG100153 and CDCA resulted in an additive
induction of apoC-II mRNA (Fig. 1D). To determine bile acid
specificity, HepG2-FXR cells were incubated for 24 h in the
presence of various bile acids. The rank order of potency of bile acids
that function to induce apoC-II mRNA (Fig. 1E; CDCA > deoxycholic
acid (DCA) > lithocholic acid (LCA) >cholic acid (CA)]
matches their activity as FXR agonists (9). ApoC-II mRNA
levels also increased in response to androsterone (Fig. 1E) and
GW4064 (data not shown), consistent with reports that these compounds
activate FXR (16, 19). Preliminary results indicate that
the induction of apoC-II mRNA in response to CDCA is unaffected by
cycloheximide treatment (data not shown), suggesting that CDCA
activates transcription of the apoC-II gene by a process that does not
require continued protein synthesis. Taken together, these observations
demonstrate that apoC-II mRNA levels are induced in a human
hepatoma-derived cell by a mechanism that requires FXR and ligands for
either FXR and/or RXR.
Identification of an FXRE Within the Hepatic Control Region
(HCR)
The human hepatic control regions, HCR.1 and HCR.2, were
originally identified in a series of elegant studies
(20, 21, 22, 23). Using transgenic mice that contained 45 kb of
human genomic DNA, Allan et al. (24)
demonstrated that both HCR.1 and HCR.2 were critical for the hepatic
expression of the apoE/C-I/C-IV/C-II gene cluster. Vorgia et
al. (25) then used promoter reporter genes
under the control of the apoC-II proximal promoter and the HCR to
demonstrate that the HCRs contained elements necessary for maximal
hepatic expression of the apoC-II gene. HCR.1 and HCR.2 have 85%
sequence identity and are located approximately 22 kb and 11 kb
upstream of the apoC-II transcriptional start site, respectively (Fig. 2A) (24).
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). We then used recombinant human (h) RXR
and FXR proteins in
EMSAs to determine whether the FXR/RXR heterodimer can bind to
these potential FXREs (Fig. 2). Recombinant FXR/RXR bound to a
radiolabeled probe containing IR-1A but not to probes containing
sequences corresponding to IR-1B or IR-1C (Fig. 2B). Probes containing
an Ecdysone response element (EcRE) or idealized IR-1, to which
FXR/RXR is known to bind (4, 5), served as positive
controls. No shifted DNA-protein complex was observed when either FXR
or RXR was omitted from the EMSAs or when three mutations were
introduced into the core sequence of IR-1A (mutIR-1A) (Fig. 2C).
These data are consistent with a requirement for the presence of both
FXR and RXR to form a stable complex with the FXRE identified in the
HCR.1 and HCR.2. Competition assays were also performed to compare the
relative affinity of FXR/RXR for the IR-1A and the previously
characterized EcRE (4, 5); a
32P-labeled probe containing the IR-1A sequence
was incubated in the presence of increasing amounts of unlabeled IR-1A,
mutIR-1A, or EcRE. The results demonstrate that the unlabeled wild-type
IR-1A and EcRE were equally effective competitors (Fig. 2D). In
contrast, the formation of the shifted complex containing radiolabeled
IR-1A probe was unaffected by the presence of the unlabeled DNA
containing the mutated IR-1A (Fig. 2D).
FXR Transactivates the Hepatic Control Region FXRE (IR-1A) in HepG2
Cells
HCR.1 and HCR.2 have previously been identified as important
enhancers that control hepatic expression of apoE, C-I, C-IV and C-II
(20, 25, 26). The data of Fig. 2 suggest that the FXRE in
HCR.1 and HCR.2 may be important for regulated transcription of apoC-II
in response to FXR and its ligands. To test this hypothesis,
we constructed luciferase reporter genes under the control of either
the apoC-II proximal promoter, the HCR.1, or two copies of either the
wild-type or mutant IR-1A (Fig. 3). Each
reporter construct was transiently transfected into HepG2 cells in the
presence or absence of plasmids encoding RXR and FXR or VP16-FXR, and
the cells were treated with the indicated ligands. VP16-FXR is expected
to be constitutively active as a result of the strong activation domain
of VP16. The data of Fig. 3A show that VP16-FXR induces the HCR.1
reporter construct even in the absence of ligand. In contrast, no
induction was observed when VP16-FXR was coexpressed with the C-II
proximal promoter reporter gene (Fig. 3A).
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shows that a reporter gene controlled by 2xIR-1A is activated
>90 fold by VP16-FXR and RXR. In contrast, no induction of the
reporter gene was observed when three mutations were incorporated into
the IR-1A sequence (Fig. 3B, 2xMutIR-1a). The data of Fig. 3C confirm
and extend these later studies and demonstrate that the
2xIR-1A-luciferase reporter is activated 10- to 27-fold by ligands for
FXR and/or RXR. This induction is dependent on coexpression of FXR and
is abolished when three mutations are introduced into the IR-1A
sequence (Fig. 3C). The thymidine kinase (TK)-luciferase empty vector
was not induced under these conditions (Fig. 3C). These data, taken
together with those of Fig. 2, demonstrate that the FXRE (IR-1A),
identified in both the HCR.1 and HCR.2 enhancer elements (Fig. 2A), is
functional when placed upstream of a heterologous promoter. These data
suggest that these two FXREs, contained within the two 319-bp enhancers
that are necessary for hepatic expression of apoC-II mRNA, are involved
in the transcriptional activation of the apoC-II gene in response to
FXR and an FXR-activating ligand.
Hepatic ApoC-II and PLTP mRNAs Are Induced in Vivo
by Bile Acids by a Process That Requires FXR
The results described above demonstrate that FXR ligands activate
transcription of the apoC-II gene in cultured HepG2 cells. We next used
wild-type or FXR null mice to determine whether cholic acid, an FXR
ligand (8, 10), could induce these genes
in vivo. The data of Fig. 4A
demonstrate that apoC-II and PLTP mRNAs are induced in wild-type mice
upon feeding a 1% cholic acid diet for 5 d, and that the
induction of both mRNAs is attenuated in FXR null mice. Figure 4B shows
the relative apoC-II and PLTP mRNA levels that have been corrected for
ß-actin levels. These results provide evidence that FXR and its
ligands directly regulate the expression of genes involved in
lipoprotein metabolism in vivo.
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). The latter two diets have been
used in numerous studies to induce atherosclerosis in mice. Hepatic
apoC-II and PLTP mRNAs were detectable in mice fed the control diet,
and both apoC-II and PLTP mRNAs were induced significantly when the
diet was supplemented with cholic acid (Fig. 5A, lane 2 vs.
1). In contrast, apoC-II and PLTP mRNAs were not induced when the mice
were fed a diet containing fat and cholesterol in the absence of cholic
acid (Fig. 5A, lane 3 vs. 1). We previously observed that
PLTP mRNA levels were induced when cultured liver cells were exposed to
ligands for FXR (5). The data of Fig. 5A extend these
earlier studies and demonstrate that PLTP mRNAs are induced in
vivo in response to a cholic acid-containing diet.
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shows that plasma
triglyceride levels (solid bars) decline 
50% when
mice are fed a diet enriched in cholic acid, cholesterol, and fat,
whereas plasma cholesterol levels increase > 2-fold (compare
panel A vs. B). In contrast, both triglyceride and
cholesterol levels increased 146% and 57%, respectively, when mice
were fed a diet enriched in fat and cholesterol, but no cholic acid
(Fig. 5B, panel C vs. A). Thus, inclusion of cholic acid to
the high-fat and cholesterol diet results in an approximate 4-fold
decrease in plasma triglyceride levels, but only a minor change in
plasma cholesterol levels (Fig. 5B, panel B vs. C).
Preliminary results indicate that this effect is independent of dietary
fat; when mice were fed diets supplemented with cholic acid and
cholesterol, in the absence of fat, we observed a 64% decrease in
plasma triglyceride levels and a 110% increase in plasma cholesterol
levels as compared with mice fed a normal chow diet (data not
shown). |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Based upon gel shift and competition studies, a potential FXRE (termed
IR-1A) was identified in the HCR of the apoE/C-I/C-IV/C-II gene
cluster. The affinity of FXR/RXR for IR-1A is similar to that of a well
characterized FXRE termed the EcRE (Fig. 2) (4, 5). There
are two hepatic control regions, HCR.1 and HCR.2, within the human gene
cluster that mediate the liver-specific expression of the
apoE/C-I/C-IV/C-II locus (24, 25). HCR.1 and HCR.2 are
each approximately 350 bp and have >85% nucleotide identity
(24). Dang et al. (30) used
in vivo footprinting to identify seven liver-specific
protein binding sites within HCR.1. The sequence of the FXRE in HCR.1
and HCR.2 is 100% conserved and is contained within a 52-bp footprint
identified by Dang et al. (30).
Based on the presence of identical potential FXREs in both HCR.1
and HCR.2 (Fig. 2A), we constructed reporter genes containing two
copies of either the wild-type or mutant IR-1A. Figure 3 demonstrates
that multiple distinct FXR ligands and/or an RXR ligand all activate
the wild-type, but not the mutant promoter-reporter gene. The
observation that reporter genes containing the proximal apoC-II
promoter were not induced by FXR ligands (Fig. 3A), coupled with the
observation that potential FXREs in the apoC-II proximal promoter did
not form a complex in vitro with purified FXR and RXR (Fig. 2), lead us to conclude that bile acid activation of the apoC-II gene
is likely to be mediated by the FXREs present in HCR.1 and HCR.2. Since
HCR.1 and HCR.2 are reported to modulate hepatic expression of multiple
genes within the apoE/C-I/C-IV/C-II gene cluster (20, 25, 26), it is possible that other apolipoproteins are also
regulated by FXR and FXR ligands. Consistent with this proposal,
preliminary studies indicate that 1) apoE and apoA-IV mRNAs are induced
after the addition of FXR ligands to FXR expressing cells
(Kast, H., S. Jones, and P. Edwards,
unpublished data); and 2) plasma apoE protein levels are
increased in GW4064-treated rats (Winegar, D., and S. Jones,
unpublished data). Additional studies will be required to determine
whether the changes in expression of these and other apolipoproteins
result from a direct effect of FXR.
ApoC-II is an obligate cofactor for lipoprotein lipase, which in turn
is responsible for the hydrolysis of triglycerides in
chylomicrons and very low density lipoprotein. Individuals with a
homozygous deficiency of apoC-II characteristically have massive
hypertriglyceridemia (31). Interestingly, patients who
have undetectable levels of apoC-II and hyperchylomicronemia, as a
result of an A-to-G substitution at -86 of the proximal apoC-II
promoter have been described (32). Although this
substitution lies within the IR-1C element (Fig. 2A), the current
studies predict that the decrease in transcription of the apoC-II gene
in these patients is independent of FXR/RXR.
Based on a previous report (5) and the results shown
in
Figs. 1–3, we reasoned that treatment of mice with an FXR ligand
(such as cholate) should result in elevated hepatic apoC-II and
PLTP mRNA levels, and that this treatment might alter lipoprotein
levels. There is a significant induction of both apoC-II and PLTP
mRNAs, and a concomitant >50% decrease in triglyceride levels when
mice were fed a cholic acid-containing diet (Fig. 5B). These data are
consistent with two recent reports: Maloney et al.
(16) demonstrated that plasma triglyceride levels
decreased 50% when rats were treated for 7 d with the FXR
synthetic ligand GW4064, and Sinal et al. (17)
demonstrated that triglyceride levels increased in FXR null mice. The
observation that PLTP mRNA levels increased when mice are fed cholic
acid containing diets is consistent with two recent reports that showed
that the PLTP promoter contained an FXRE (5, 13), and that
induction of a reporter gene was dependent on the intact FXRE, and
ligand-activated FXR/RXR (13).
The current data demonstrate that activators of FXR result in decreased triglyceride levels and provide a mechanism to explain studies described more than 25 yr ago in which CDCA was administered to patients with gallstones (33). This treatment solubilized cholesterol-rich gallstones and also lowered plasma triglycerides (33). The current studies suggest that the administration of FXR ligands results in the coordinate induction of genes that regulate lipoprotein metabolism and lower plasma triglyceride levels. Such genes include, but are probably not limited to, apoC-II, PLTP, apoA-IV, and apoE. Based on the observations that FXR ligands both activate genes involved in lipoprotein metabolism and decrease plasma triglyceride levels and the finding that FXR null mice exhibit a "proatherogenic lipoprotein profile" (17), we hypothesize that FXR agonists may prove useful as a novel treatment for metabolic mixed dyslipidemias (low HDL, high LDL and triglycerides).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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, and VP16-FXR were gifts from Dr.
Ron Evans (Salk Institute, La Jolla, CA). The sources of other reagents
and plasmids have been noted elsewhere (5).
Cell Culture and Stable Cell Lines
The isolation and maintenance of wild-type and stably infected
HepG2s cells have been described (5).
SSH
Total RNA was isolated from HepG2-vector cells treated with DMSO
(driver) and from HepG2-FXR cells treated with 50 µM CDCA
(tester) for 24 h. The driver and tester RNA were used in SSH
using the PCR-Select Subtraction Kit (CLONTECH Laboratories, Inc., Palo Alto, CA) according to the manufacturer’s
instructions (35).
RNA Isolation and Northern Blot Hybridization
Unless otherwise indicated, HepG2-derived cell lines were
cultured in medium containing super-stripped FBS for 24 h before
the addition of ligand or DMSO (vehicle) for an additional 24 h.
Total RNA was isolated using TRIzol reagent (Life Technologies, Inc., Gaithersburg, MD) and was resolved (10 µg/per lane) on a
1% agarose/formaldehyde gel, transferred to nylon membrane, and
cross-linked to the membrane with UV light. cDNA probes were
radiolabeled with [-32P]dCTP using the
Rediprime II labeling kit (Amersham Pharmacia Biotech,
Arlington Heights, IL). Membranes were hybridized using the QuikHyb
Hybridization Solution (Stratagene) according to the
manufacturer’s protocol. Blots were normalized for variations of RNA
loading by hybridization to a control probe, either
glyceraldehyde-3-phosphate dehydrogenase, rat 18S ribosomal
cDNA, or the ribosomal protein 36B4. The RNA levels were
quantitated using a PhosphorImager (ImageQuant software,
Molecular Dynamics, Inc., Sunnyvale, CA).
EMSAs
Partially purified FXR
110 and hRXR (5)
were incubated with the binding buffer [10 mM HEPES, pH
7.9, 0.5 mM dithiothreitol, 2.5 mM
MgCl2, 0.05% (vol/vol) glycerol, 50 mg/ml nonfat
milk, and 50 mM NaCl] at room temperature for 15 min.
Labeled probe (30,000 cpm, 1.5 fmol) was added and allowed to complex
at room temperature for 30 min. Complexes were resolved by 4%
nondenaturing PAGE at 4 C for 2.5 h. The gel was dried and
analyzed by autoradiography and PhosphorImaging. The oligos used were
IR-1A 5'-gctggggcagaggtcagagacctctctggg-3',
IR-1B 5'-gaccttgggggacgtcattgccctttctgtcccc-3',
IR-1C
5'-gttctgttggccaggactttggcctagacaaaggatgggg-3'
and mutant IR-1A (mutIR-1A)
5'-gctggggcagagtgcagagatctctctggg-3' (only one
strand is shown). The wild-type or mutant IR-1 is
boldface and underlined.
Reporter Genes
The proximal promoter of apoC-II (-47 to -540 bp)
(25) was amplified from human genomic DNA using primers
5'-gggggatccggatccttccccagtgtggc-3' and
5'-ggagatctgctccacagccacaaccccat-3' and cloned into
BamHI/BglII sites of the TK-Luc vector. The HCR.1
was amplified from an HCR.1-apoCII proximal promoter clone using
primers 5'-ggggatccggcacacaggagtttctgggctca-3' and
5'-aaagatcttctcacactacctaaaccacgccaggaca-3'. The PCR product was
subsequently ligated into the TK-Luc vector at the
BamHI/BglII location. The two copy IR-1A was
generated by annealing the oligonucleotides
5'-gatcgctggggcagaggtcagagacctctctgggcccatgccaaggtcagagacctctct-3'
and
5'-gatcagagaggtctctgaccttggcatgggcccagagaggtctctgacctctgccccagc-3'
before ligation into BamHI/BglII digested TK-Luc.
The two FXR/RXR binding sites are bolded. The two copy
mutIR-1A was created in a similar manner using
5'-gatcgctggggcagagtgcagagatctctctgggcccatgccaagtgcagagatctctct-3'
and
5'-gatcagagagatctctgcacttggcatgggcccagagagatctctgcactctgccccagc-3'.
Mutations are italic boldface and
underlined.
Transient Transfections and Reporter Gene Assays
HepG2 cells were transiently transfected using the MBS Mammalian
Transfection Kit (Stratagene, La Jolla, CA), with minor
modifications. Reporter plasmid (100 ng), 50 ng pCMX-FXR, 5 ng
pCMX-RXR, and 50 ng pCMV-ß-galactosidase were transfected into
HepG2 cells in a 48-well dish. After 3.5 h the cells were treated
with 10% superstripped FBS and one of the following ligands: TTNPB
(BIOMOL Research Laboratories, Inc., Plymouth Meeting,
PA), 3,7-dihydroxy-5ß-cholanic acid (CDCA)
(Sigma, St. Louis, MO), LG100153 (synthetic RXR-agonist)
(Ligand Pharmaceuticals, Inc.), or
3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole
(GW4064) (GlaxoSmithKline, Research Triangle Park, NC). After
24 h, the cells were lysed and assayed for luciferase and
ß-galactosidase activity (5).
FXR Null Mice and Diets
The FXR null mice were generated as previously described
(17). The mice used in Fig. 4 were maintained on a
standard AIN-93G diet supplemented, where indicated, with 1% cholic
acid for 5 d. RNA was isolated and analyzed as described
previously (17).
Mice and Diets
The data of Fig. 5 were generated using C57BL/6J mice
(The Jackson Laboratory; Bar Harbor, ME). Mice were fed
Purina Mouse Chow 5001 (Ralston Purina Co., Battle Creek,
MI) ad libitum. At 3 months of age, mice (five per group)
were housed individually and fed for 3 wk either control chow (Teklad
Research Diets, Madison, WI), an atherogenic diet (21) (TD
90221), which contained 75% Purina Mouse Chow, 7.5% cocoa butter,
1.25% cholesterol, and 0.5% sodium cholate, or a Western diet (TD
94059, 7.5% cocoa butter and 1.25% cholesterol). The mice were fasted
overnight before harvesting blood for lipid determinations and tissues
for RNA isolation. Plasma total cholesterol and triglyceride
concentrations were determined by enzymatic assays (36).
The care of the mice, as well as all procedures used in this study,
were conducted in accordance with the NIH animal care guidelines.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: apoC-II, Apolipoprotein C-II; CDCA, chenodeoxycholic acid; DMSO, dimethylsulfoxide; EcRE, Ecdysone response element; FXR, farnesoid X-activated receptor; FXRE, FXR response element; HCR, hepatic control region; IR-I, inverted repeat with one nucleotide spacing between the two half-sites; IRES, internal ribosome entry site; LCA, lithocholic acid; SHP, small heterodimer partner; SSH, suppression subtractive hybridization; TK, thymidine kinase; TTNPB, 2-[E-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl] benzoic acid.
Received for publication April 20, 2001. Accepted for publication June 28, 2001.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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. Nature 395:137–143[CrossRef][Medline]
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 B. Kong, J. P. Luyendyk, O. Tawfik, and G. L. Guo Farnesoid X Receptor Deficiency Induces Nonalcoholic Steatohepatitis in Low-Density Lipoprotein Receptor-Knockout Mice Fed a High-Fat Diet J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 116 - 122. [Abstract] [Full Text] [PDF]
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 N. Stefan, K. Kantartzis, and H.-U. Haring Causes and Metabolic Consequences of Fatty Liver Endocr. Rev., December 1, 2008; 29(7): 939 - 960. [Abstract] [Full Text] [PDF]
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 R. Gineste, A. Sirvent, R. Paumelle, S. Helleboid, A. Aquilina, R. Darteil, D. W. Hum, J.-C. Fruchart, and B. Staels Phosphorylation of Farnesoid X Receptor by Protein Kinase C Promotes Its Transcriptional Activity Mol. Endocrinol., November 1, 2008; 22(11): 2433 - 2447. [Abstract] [Full Text] [PDF]
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I. Kim, S.-H. Ahn, T. Inagaki, M. Choi, S. Ito, G. L. Guo, S. A. Kliewer, and F. J. Gonzalez Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine J. Lipid Res., December 1, 2007; 48(12): 2664 - 2672. [Abstract] [Full Text] [PDF]
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 L. Vila, N. Roglans, M. Alegret, A. Camins, M. Pallas, R. M. Sanchez, M. Vazquez-Carrera, and J. C. Laguna Hypertriglyceridemia and Hepatic Steatosis in Senescence-Accelerated Mouse Associate to Changes in Lipid-Related Gene Expression J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2007; 62(11): 1219 - 1227. [Abstract] [Full Text] [PDF]
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M. L. Hubbert, Y. Zhang, F. Y. Lee, and P. A. Edwards Regulation of Hepatic Insig-2 by the Farnesoid X Receptor Mol. Endocrinol., June 1, 2007; 21(6): 1359 - 1369. [Abstract] [Full Text] [PDF]
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 T. Hu, M. Chouinard, A. L. Cox, P. Sipes, M. Marcelo, J. Ficorilli, S. Li, H. Gao, T. P. Ryan, M. D. Michael, et al. Farnesoid X Receptor Agonist Reduces Serum Asymmetric Dimethylarginine Levels through Hepatic Dimethylarginine Dimethylaminohydrolase-1 Gene Regulation J. Biol. Chem., December 29, 2006; 281(52): 39831 - 39838. [Abstract] [Full Text] [PDF]
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A. Das, M. E. Fernandez-Zapico, S. Cao, J. Yao, S. Fiorucci, R. P. Hebbel, R. Urrutia, and V. H. Shah Disruption of an SP2/KLF6 Repression Complex by SHP Is Required for Farnesoid X Receptor-induced Endothelial Cell Migration J. Biol. Chem., December 22, 2006; 281(51): 39105 - 39113. [Abstract] [Full Text] [PDF]
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 D. D. Moore, S. Kato, W. Xie, D. J. Mangelsdorf, D. R. Schmidt, R. Xiao, and S. A. Kliewer International Union of Pharmacology. LXII. The NR1H and NR1I Receptors: Constitutive Androstane Receptor, Pregnene X Receptor, Farnesoid X Receptor {alpha}, Farnesoid X Receptor beta, Liver X Receptor {alpha}, Liver X Receptor beta, and Vitamin D Receptor Pharmacol. Rev., December 1, 2006; 58(4): 742 - 759. [Abstract] [Full Text] [PDF]
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 Y. Zhang, X. Wang, C. Vales, F. Y. Lee, H. Lee, A. J. Lusis, and P. A. Edwards FXR Deficiency Causes Reduced Atherosclerosis in Ldlr-/- Mice Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2316 - 2321. [Abstract] [Full Text] [PDF]
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 S. Wang, K. Lai, F. J. Moy, A. Bhat, H. B. Hartman, and M. J. Evans The Nuclear Hormone Receptor Farnesoid X Receptor (FXR) Is Activated by Androsterone Endocrinology, September 1, 2006; 147(9): 4025 - 4033. [Abstract] [Full Text] [PDF]
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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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B. Desvergne, L. Michalik, and W. Wahli Transcriptional Regulation of Metabolism Physiol Rev, April 1, 2006; 86(2): 465 - 514. [Abstract] [Full Text] [PDF]
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 Y. Zhang, F. Y. Lee, G. Barrera, H. Lee, C. Vales, F. J. Gonzalez, T. M. Willson, and P. A. Edwards Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice PNAS, January 24, 2006; 103(4): 1006 - 1011. [Abstract] [Full Text] [PDF]
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H. Lee, Y. Zhang, F. Y. Lee, S. F. Nelson, F. J. Gonzalez, and P. A. Edwards FXR regulates organic solute transporters {alpha} and {alpha} in the adrenal gland, kidney, and intestine J. Lipid Res., January 1, 2006; 47(1): 201 - 214. [Abstract] [Full Text] [PDF]
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E. A. Hanniman, G. Lambert, T. C. McCarthy, and C. J. Sinal Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice J. Lipid Res., December 1, 2005; 46(12): 2595 - 2604. [Abstract] [Full Text] [PDF]
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X. Prieur, F. G. Schaap, H. Coste, and J. C. Rodriguez Hepatocyte Nuclear Factor-4{alpha} Regulates the Human Apolipoprotein AV Gene: Identification of a Novel Response Element and Involvement in the Control by Peroxisome Proliferator-Activated Receptor-{gamma} Coactivator-1{alpha}, AMP-Activated Protein Kinase, and Mitogen-Activated Protein Kinase Pathway Mol. Endocrinol., December 1, 2005; 19(12): 3107 - 3125. [Abstract] [Full Text] [PDF]
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T. Claudel, B. Staels, and F. Kuipers The Farnesoid X Receptor: A Molecular Link Between Bile Acid and Lipid and Glucose Metabolism Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2020 - 2030. [Abstract] [Full Text] [PDF]
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F. Y. Lee, H. R. Kast-Woelbern, J. Chang, G. Luo, S. A. Jones, M. C. Fishbein, and P. A. Edwards {alpha}-Crystallin Is a Target Gene of the Farnesoid X-activated Receptor in Human Livers J. Biol. Chem., September 9, 2005; 280(36): 31792 - 31800. [Abstract] [Full Text] [PDF]
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 S W C van Mil, R H J Houwen, and L W J Klomp Genetics of familial intrahepatic cholestasis syndromes J. Med. Genet., June 1, 2005; 42(6): 449 - 463. [Abstract] [Full Text] [PDF]
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J. Li, P. C. Pircher, I. G. Schulman, and S. K. Westin Regulation of Complement C3 Expression by the Bile Acid Receptor FXR J. Biol. Chem., March 4, 2005; 280(9): 7427 - 7434. [Abstract] [Full Text] [PDF]
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A. M. Anisfeld, H. R. Kast-Woelbern, H. Lee, Y. Zhang, F. Y. Lee, and P. A. Edwards Activation of the nuclear receptor FXR induces fibrinogen expression: a new role for bile acid signaling J. Lipid Res., March 1, 2005; 46(3): 458 - 468. [Abstract] [Full Text] [PDF]
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K. R. Stayrook, K. S. Bramlett, R. S. Savkur, J. Ficorilli, T. Cook, M. E. Christe, L. F. Michael, and T. P. Burris Regulation of Carbohydrate Metabolism by the Farnesoid X Receptor Endocrinology, March 1, 2005; 146(3): 984 - 991. [Abstract] [Full Text] [PDF]
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R. S. Savkur, J. S. Thomas, K. S. Bramlett, Y. Gao, L. F. Michael, and T. P. Burris Ligand-Dependent Coactivation of the Human Bile Acid Receptor FXR by the Peroxisome Proliferator-Activated Receptor {gamma} Coactivator-1{alpha} J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 170 - 178. [Abstract] [Full Text] [PDF]
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A. Sirvent, A. J. M. Verhoeven, H. Jansen, V. Kosykh, R. J. Darteil, D. W. Hum, J.-C. Fruchart, and B. Staels Farnesoid X receptor represses hepatic lipase gene expression J. Lipid Res., November 1, 2004; 45(11): 2110 - 2115. [Abstract] [Full Text] [PDF]
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 D. S. Ory Nuclear Receptor Signaling in the Control of Cholesterol Homeostasis: Have the Orphans Found a Home? Circ. Res., October 1, 2004; 95(7): 660 - 670. [Abstract] [Full Text] [PDF]
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I. Pineda Torra, L. P. Freedman, and M. J. Garabedian Identification of DRIP205 as a Coactivator for the Farnesoid X Receptor J. Biol. Chem., August 27, 2004; 279(35): 36184 - 36191. [Abstract] [Full Text] [PDF]
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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] [PDF]
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Y. Zhang, J. J. Repa, Y. Inoue, G. P. Hayhurst, F. J. Gonzalez, and D. J. Mangelsdorf Identification of a Liver-Specific Uridine Phosphorylase that Is Regulated by Multiple Lipid-Sensing Nuclear Receptors Mol. Endocrinol., April 1, 2004; 18(4): 851 - 862. [Abstract] [Full Text] [PDF]
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 D. Duran-Sandoval, G. Mautino, G. Martin, F. Percevault, O. Barbier, J.-C. Fruchart, F. Kuipers, and B. Staels Glucose Regulates the Expression of the Farnesoid X Receptor in Liver Diabetes, April 1, 2004; 53(4): 890 - 898. [Abstract] [Full Text] [PDF]
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J.-L. Lew, A. Zhao, J. Yu, L. Huang, N. de Pedro, F. Pelaez, S. D. Wright, and J. Cui The Farnesoid X Receptor Controls Gene Expression in a Ligand- and Promoter-selective Fashion J. Biol. Chem., March 5, 2004; 279(10): 8856 - 8861. [Abstract] [Full Text] [PDF]
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 Y. Zhang, L. W. Castellani, C. J. Sinal, F. J. Gonzalez, and P. A. Edwards Peroxisome proliferator-activated receptor-{gamma} coactivator 1{alpha} (PGC-1{alpha}) regulates triglyceride metabolism by activation of the nuclear receptor FXR Genes & Dev., January 15, 2004; 18(2): 157 - 169. [Abstract] [Full Text] [PDF]
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L. Huang, A. Zhao, J.-L. Lew, T. Zhang, Y. Hrywna, J. R. Thompson, N. de Pedro, I. Royo, R. A. Blevins, F. Pelaez, et al. Farnesoid X Receptor Activates Transcription of the Phospholipid Pump MDR3 J. Biol. Chem., December 19, 2003; 278(51): 51085 - 51090. [Abstract] [Full Text] [PDF]
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E. Kim, S. Xie, S.-D. Yeh, Y.-F. Lee, L. L. Collins, Y.-C. Hu, C.-R. Shyr, X.-M. Mu, N.-C. Liu, Y.-T. Chen, et al. Disruption of TR4 Orphan Nuclear Receptor Reduces the Expression of Liver Apolipoprotein E/C-I/C-II Gene Cluster J. Biol. Chem., November 21, 2003; 278(47): 46919 - 46926. [Abstract] [Full Text] [PDF]
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G. L. Guo, G. Lambert, M. Negishi, J. M. Ward, H. B. Brewer Jr., S. A. Kliewer, F. J. Gonzalez, and C. J. Sinal Complementary Roles of Farnesoid X Receptor, Pregnane X Receptor, and Constitutive Androstane Receptor in Protection against Bile Acid Toxicity J. Biol. Chem., November 14, 2003; 278(46): 45062 - 45071. [Abstract] [Full Text] [PDF]
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T. Kok, C. V. Hulzebos, H. Wolters, R. Havinga, L. B. Agellon, F. Stellaard, B. Shan, M. Schwarz, and F. Kuipers Enterohepatic Circulation of Bile Salts in Farnesoid X Receptor-deficient Mice: EFFICIENT INTESTINAL BILE SALT ABSORPTION IN THE ABSENCE OF ILEAL BILE ACID-BINDING PROTEIN J. Biol. Chem., October 24, 2003; 278(43): 41930 - 41937. [Abstract] [Full Text] [PDF]
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B. G. Bhat, S. R. Rapp, J. A. Beaudry, N. Napawan, D. N. Butteiger, K. A. Hall, C. L. Null, Y. Luo, and B. T. Keller Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE-/- mice by SC-435 J. Lipid Res., September 1, 2003; 44(9): 1614 - 1621. [Abstract] [Full Text] [PDF]
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A. Zhao, J.-L. Lew, L. Huang, J. Yu, T. Zhang, Y. Hrywna, J. R. Thompson, N. de Pedro, R. A. Blevins, F. Pelaez, et al. Human Kininogen Gene Is Transactivated by the Farnesoid X Receptor J. Biol. Chem., August 1, 2003; 278(31): 28765 - 28770. [Abstract] [Full Text] [PDF]
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P. C. Pircher, J. L. Kitto, M. L. Petrowski, R. K. Tangirala, E. D. Bischoff, I. G. Schulman, and S. K. Westin Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation J. Biol. Chem., July 18, 2003; 278(30): 27703 - 27711. [Abstract] [Full Text] [PDF]
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X. Prieur, H. Coste, and J. C. Rodriguez The Human Apolipoprotein AV Gene Is Regulated by Peroxisome Proliferator-activated Receptor-{alpha} and Contains a Novel Farnesoid X-activated Receptor Response Element J. Biol. Chem., July 3, 2003; 278(28): 25468 - 25480. [Abstract] [Full Text] [PDF]
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A. Cachefo, P. Boucher, E. Dusserre, P. Bouletreau, M. Beylot, and C. Chambrier Stimulation of cholesterol synthesis and hepatic lipogenesis in patients with severe malabsorption J. Lipid Res., July 1, 2003; 44(7): 1349 - 1354. [Abstract] [Full Text] [PDF]
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A. M. Anisfeld, H. R. Kast-Woelbern, M. E. Meyer, S. A. Jones, Y. Zhang, K. J. Williams, T. Willson, and P. A. Edwards Syndecan-1 Expression Is Regulated in an Isoform-specific Manner by the Farnesoid-X Receptor J. Biol. Chem., May 23, 2003; 278(22): 20420 - 20428. [Abstract] [Full Text] [PDF]
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 B. A. Laffitte, S. B. Joseph, M. Chen, A. Castrillo, J. Repa, D. Wilpitz, D. Mangelsdorf, and P. Tontonoz The Phospholipid Transfer Protein Gene Is a Liver X Receptor Target Expressed by Macrophages in Atherosclerotic Lesions Mol. Cell. Biol., March 15, 2003; 23(6): 2182 - 2191. [Abstract] [Full Text] [PDF]
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J. Cui, L. Huang, A. Zhao, J.-L. Lew, J. Yu, S. Sahoo, P. T. Meinke, I. Royo, F. Pelaez, and S. D. Wright Guggulsterone Is a Farnesoid X Receptor Antagonist in Coactivator Association Assays but Acts to Enhance Transcription of Bile Salt Export Pump J. Biol. Chem., March 14, 2003; 278(12): 10214 - 10220. [Abstract] [Full Text] [PDF]
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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] [PDF]
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I. Pineda Torra, T. Claudel, C. Duval, V. Kosykh, J.-C. Fruchart, and B. Staels Bile Acids Induce the Expression of the Human Peroxisome Proliferator-Activated Receptor {alpha} Gene via Activation of the Farnesoid X Receptor Mol. Endocrinol., February 1, 2003; 17(2): 259 - 272. [Abstract] [Full Text] [PDF]
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G. Lambert, M. J. A. Amar, G. Guo, H. B. Brewer Jr., F. J. Gonzalez, and C. J. Sinal The Farnesoid X-receptor Is an Essential Regulator of Cholesterol Homeostasis J. Biol. Chem., January 17, 2003; 278(4): 2563 - 2570. [Abstract] [Full Text] [PDF]
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Y. Zhang, H. R. Kast-Woelbern, and P. A. Edwards Natural Structural Variants of the Nuclear Receptor Farnesoid X Receptor Affect Transcriptional Activation J. Biol. Chem., January 3, 2003; 278(1): 104 - 110. [Abstract] [Full Text] [PDF]
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P. A. Mak, H. R. Kast-Woelbern, A. M. Anisfeld, and P. A. Edwards Identification of PLTP as an LXR target gene and apoE as an FXR target gene reveals overlapping targets for the two nuclear receptors J. Lipid Res., December 1, 2002; 43(12): 2037 - 2041. [Abstract] [Full Text] [PDF]
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P. A. Mak, B. A. Laffitte, C. Desrumaux, S. B. Joseph, L. K. Curtiss, D. J. Mangelsdorf, P. Tontonoz, and P. A. Edwards Regulated Expression of the Apolipoprotein E/C-I/C-IV/C-II Gene Cluster in Murine and Human Macrophages. A CRITICAL ROLE FOR NUCLEAR LIVER X RECEPTORS alpha AND beta J. Biol. Chem., August 23, 2002; 277(35): 31900 - 31908. [Abstract] [Full Text] [PDF]
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J. Y. L. Chiang Bile Acid Regulation of Gene Expression: Roles of Nuclear Hormone Receptors Endocr. Rev., August 1, 2002; 23(4): 443 - 463. [Abstract] [Full Text] [PDF]
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J. Cui, T. S. Heard, J. Yu, J.-L. Lo, L. Huang, Y. Li, J. M. Schaeffer, and S. D. Wright The Amino Acid Residues Asparagine 354 and Isoleucine 372 of Human Farnesoid X Receptor Confer the Receptor with High Sensitivity to Chenodeoxycholate J. Biol. Chem., July 12, 2002; 277(29): 25963 - 25969. [Abstract] [Full Text] [PDF]
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P. A. Edwards, H. R. Kast, and A. M. Anisfeld BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis J. Lipid Res., January 1, 2002; 43(1): 2 - 12. [Abstract] [Full Text] [PDF]
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H. R. Kast, B. Goodwin, P. T. Tarr, S. A. Jones, A. M. Anisfeld, C. M. Stoltz, P. Tontonoz, S. Kliewer, T. M. Willson, and P. A. Edwards Regulation of Multidrug Resistance-associated Protein 2 (ABCC2) by the Nuclear Receptors Pregnane X Receptor, Farnesoid X-activated Receptor, and Constitutive Androstane Receptor J. Biol. Chem., January 18, 2002; 277(4): 2908 - 2915. [Abstract] [Full Text] [PDF]
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