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Molecular Endocrinology, doi:10.1210/me.2002-0120
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Molecular Endocrinology 17 (2): 259-272
Copyright © 2003 by The Endocrine Society

Bile Acids Induce the Expression of the Human Peroxisome Proliferator-Activated Receptor {alpha} Gene via Activation of the Farnesoid X Receptor

Inés Pineda Torra1,2, Thierry Claudel1, Caroline Duval, Vladimir Kosykh, Jean-Charles Fruchart and Bart Staels

U.545 Institut National de la Santé et de la Recherche Médicale (I.P.T., T.C., C.D., J.-C.F., B.S.), Département d’Athérosclérose, Institut Pasteur de Lille, 59019 Lille, France; the Faculté de Pharmacie, Université de Lille II, 59006 Lille, France; and Institute of Experimental Cardiology (V.K.), Russian Cardiology Complex, Moscow 121552, Russia

Address all correspondence and requests for reprints to: Bart Staels, U.545 Institut National de la Santé et de la Recherche Médicale, Institut Pasteur de Lille, 1 Rue Calmette BP245, 59019 Lille, France. E-mail: bart.staels{at}pasteur-lille.fr.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
Peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) is a nuclear receptor that controls lipid and glucose metabolism and exerts antiinflammatory activities. PPAR{alpha} is also reported to influence bile acid formation and bile composition. Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that mediates the effects of bile acids on gene expression and plays a major role in bile acid and possibly also in lipid metabolism. Thus, both PPAR{alpha} and FXR appear to act on common metabolic pathways. To determine the existence of a molecular cross-talk between these two nuclear receptors, the regulation of PPAR{alpha} expression by bile acids was investigated. Incubation of human hepatoma HepG2 cells with the natural FXR ligand chenodeoxycholic acid (CDCA) as well as with the nonsteroidal FXR agonist GW4064 resulted in a significant induction of PPAR{alpha} mRNA levels. In addition, hPPAR{alpha} gene expression was up-regulated by taurocholic acid in human primary hepatocytes. Cotransfection of FXR/retinoid X receptor in the presence of CDCA led to up to a 3-fold induction of human PPAR{alpha} promoter activity in HepG2 cells. Mutation analysis identified a FXR response element in the human PPAR{alpha} promoter ({alpha}-FXR response element ({alpha}FXRE)] that mediates bile acid regulation of this promoter. FXR bound the {alpha}FXRE site as demonstrated by gel shift analysis, and CDCA specifically increased the activity of a heterologous promoter driven by four copies of the {alpha}FXRE. In contrast, neither the murine PPAR{alpha} promoter, in which the {alpha}FXRE is not conserved, nor a mouse {alpha}FXRE-driven heterologous reporter, were responsive to CDCA treatment. Moreover, PPAR{alpha} expression was not regulated in taurocholic acid-fed mice. Finally, induction of hPPAR{alpha} mRNA levels by CDCA resulted in an enhanced induction of the expression of the PPAR{alpha} target gene carnitine palmitoyltransferase I by PPAR{alpha} ligands. In concert, these results demonstrate that bile acids stimulate PPAR{alpha} expression in a species-specific manner via a FXRE located within the human PPAR{alpha} promoter. These results provide molecular evidence for a cross-talk between the FXR and PPAR{alpha} pathways in humans.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RESULTS
 DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
CHOLESTEROL HOMEOSTASIS IS maintained by the coordinated regulation of cholesterol absorption, biosynthesis, and catabolism. Dysregulation of these pathways may result in cholesterol excess, leading to the development of disorders such as atherosclerosis and gallstone formation. Bile acid (BA) formation, the principal pathway by which the body catabolizes cholesterol, is an essential step in the maintenance of cholesterol homeostasis (1). In addition to facilitating the excretion of hepatic cholesterol into the bile, BAs display essential detergent actions in the intestine, where they emulsify hydrophobic nutrients such as lipids and fat-soluble vitamins, and in the liver, where they solubilize metabolites such as bilirubin (1).

Recently, BAs have also been shown to exert signaling activities leading to the modulation of the expression of genes involved in their own synthesis and transport (2). BAs are physiological ligands and activators of the farnesoid X receptor (FXR, NR1H4), a transcription factor belonging to the nuclear receptor superfamily (3, 4, 5). FXR expression is restricted to liver, kidney, colon, small intestine, and the adrenal cortex (6). FXR binds as a heterodimer with retinoid X receptor (RXR) to response elements [FXR response elements (FXREs)] consisting of an inverted repeat (IR) of the canonical AGGTCA hexanucleotide core motif spaced by 0 (IR-0) (7) or 1 bp (IR-1) (6, 8). FXR/RXR heterodimers can also recognize other DNA motifs with varying affinity, such as direct repeats (DRs) of this core sequence with different spacing (9). In addition, an everted repeat (ER) of the core motif separated by eight nucleotides (ER-8) was recently shown to mediate the induction of the multidrug resistant-associated protein 2 by BAs (10). Finally, it was recently shown that apolipoprotein AI is regulated by FXR via a monomeric form (11). Therefore, reported functional FXREs display a large heterogeneity.

BAs exert a negative feedback regulation on their own synthesis by repressing the transcription of the gene coding for cholesterol 7{alpha}-hydroxylase (CYP7A1), the first and rate-limiting enzyme in the classic hepatic BA biosynthetic pathway (12). Repression of CYP7A1 requires FXR expression (13) and is, at least in part, achieved indirectly via a coordinated regulatory cascade involving FXR-mediated induction of the nuclear receptor small heterodimer partner (NR0B2), which, in turn, inhibits the activity of the tissue-specific factor liver receptor homolog-1 (LRH-1, NR5A2), a transcription factor controlling hepatic expression of CYP7A1 (14, 15). Cholesterol 12{alpha}-hydroxylase, the enzyme responsible for cholic acid synthesis, is also under negative control by BAs (16) in an FXR-dependent manner (13) via a similar mechanism (17). Cholesterol 12{alpha}-hydroxylase modulates the ratio of cholic acid to chenodeoxycholic acid and hence determines the hydrophobicity of the circulating BA pool. BAs furthermore influence their transport by regulating a number of cellular BA transporters. The ileal-BA-binding protein (I-BABP) is a cytosolic protein that binds BAs with high affinity and may facilitate the movement of BAs across enterocytes (18). I-BABP transcription is induced by BAs via FXR (5, 19). Recently, studies on FXR-deficient mice indicated that, in addition to I-BABP, the expression of other BA transport proteins, including the sodium taurocholate transporting polypeptide (NTCP) and the bile salt export pump are regulated by BAs in a FXR-dependent manner (13). The bile salt export pump was recently further characterized as a bona fide FXR target gene (20).

More surprisingly, targeted disruption of FXR demonstrated that this nuclear receptor also controls lipid metabolism. Indeed, FXR-deficient mice exhibit elevated levels of hepatic cholesterol and triglycerides, as well as increased plasma levels of apolipoprotein B-containing lipoproteins (13). Moreover, FXR ligands reduce plasma triglycerides in vivo (13, 21, 22) and regulate the expression of the apolipoprotein CII gene (21), a cofactor for lipoprotein lipase, the enzyme that mediates triglyceride hydrolysis in triglyceride-rich particles. In addition, FXR has also been shown to mediate BA induction of phospholipid transfer protein (23) and repression of apolipoprotein AI (11), which play an important role in high density lipoprotein metabolism (24).

Peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) is a nuclear receptor that controls lipid and lipoprotein metabolism (25). PPAR{alpha} heterodimerizes with RXR to bind to PPAR response elements consisting of a DR sequence spaced by 1 or 2 bp (DR1 or DR2) (25). Fatty acid derivatives are natural ligands for PPAR{alpha} (26). Furthermore, PPAR{alpha} mediates the lipid-lowering action of the hypolipidemic fibrate drugs (27). PPAR{alpha} regulates intra- and extracellular lipid metabolism, stimulates the reverse cholesterol transport pathway (28, 29), modulates glucose and energy homeostasis (25, 30, 31), and possesses antiinflammatory properties (32). These actions likely account for the antiatherogenic properties of PPAR{alpha} activators in humans (33, 34, 35, 36). Interestingly, PPAR{alpha} was recently shown to regulate BA synthesis and bile composition. PPAR{alpha} ligands regulate CYP7A1 activity and mRNA in rodents as well as in humans (37, 38, 39, 40, 41, 42, 43). Furthermore, PPAR{alpha} induces the expression of cholesterol 12{alpha}-hydroxylase, thereby increasing the ratio of cholic acid to chenodeoxycholic acid in the bile (44).

Altogether, these data suggest that PPAR{alpha} and FXR may modulate common metabolic pathways. To investigate the existence of a molecular cross-talk between the PPAR{alpha} and FXR pathways, regulation of human PPAR{alpha} (hPPAR{alpha}) gene expression by BAs was evaluated. Our results demonstrate that natural and synthetic FXR ligands induce hPPAR{alpha} mRNA levels in human hepatic cells but not in murine liver. Furthermore, BA-activated FXR enhances hPPAR{alpha} transcription through an FXRE located within the hPPAR{alpha} promoter that is not conserved in the mouse PPAR{alpha} promoter. Finally, induction of hPPAR{alpha} mRNA levels by chenodeoxycholic acid (CDCA) enhanced the response of the hPPAR{alpha} target gene carnitine palmitoyltransferase I (CPT-I) to its ligands. These results provide molecular evidence for a cross-talk between the FXR and PPAR{alpha} pathways.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
DISCUSSION
 MATERIALS AND METHODS
 REFERENCES
 
FXR Agonists Induce hPPAR{alpha} mRNA Levels in Human Hepatoma HepG2 Cells and Primary Hepatocytes
To study whether BAs influence the expression of hPPAR{alpha}, human hepatoma HepG2 cells were incubated for 48 h with increasing concentrations of CDCA, a lipophilic BA that does not require the presence of the BA transporter NTCP for its cellular uptake. CDCA treatment led to an increase in hPPAR{alpha} mRNA levels in a dose-dependent manner, as assessed by ribonuclease (RNase) protection analysis (Fig. 1AGo). Because BAs, in addition to their actions via FXR, may also trigger alternative regulatory pathways, the effect of a specific nonsteroidal FXR agonist on PPAR{alpha} gene expression was investigated. Treatment of HepG2 cells with GW4064 for 48 h increased hPPAR{alpha} mRNA levels as measured by quantitative RT-PCR analysis (Fig. 1BGo). Furthermore, regulation of hPPAR{alpha} gene expression by the hydrophilic conjugated BA, taurocholic acid (TCA), was assessed in primary human hepatocytes, which express NTCP and thus can internalize TCA. Treatment of hepatocytes with TCA (100 µM) induced hPPAR{alpha} mRNA expression by almost 3-fold (Fig. 1CGo). BA regulation of PPAR{alpha} was also examined in vivo in mice. Hepatic PPAR{alpha} mRNA levels measured by Northern blot analysis were not significantly different in 0.5% TCA-fed mice vs. mice fed a control diet (0.94 ± 0.49 and 1.00 ± 0.20, respectively). This is in agreement with the previously reported absence of PPAR{alpha} regulation in cholic acid-treated mice compared with control chow-fed mice (45). Altogether these observations indicate that ligands for FXR increase PPAR{alpha} mRNA levels in humans but not in mice.



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  		Figure 1. CDCA Induces PPAR{alpha} Expression in Human Hepatoma HepG2 Cells and Primary Hepatocytes

A, Total RNA was prepared from HepG2 cells treated with vehicle (-) or CDCA at the indicated concentrations. RNA was subjected to RNase protection analysis using specific PPAR{alpha} and 36B4 probes as described in Materials and Methods. B, HepG2 cells were treated with either vehicle (-) or GW4064 (5 µM). Total RNA was extracted and PPAR{alpha} and 28S gene expression were quantified by real-time PCR analysis. hPPAR{alpha} mRNA normalized to 28S levels is expressed relative to untreated cells (mean ± SD, n = 3). C, Total RNA was prepared from human primary hepatocytes treated with vehicle (-) or TCA (100 µM) as indicated. PPAR{alpha} and 28S mRNA levels were measured by real-time PCR analysis. hPPAR{alpha} mRNA normalized to 28S levels is expressed as in panel B.

 
BAs Induce hPPAR{alpha} Promoter Activity via the Nuclear Receptor FXR
Next, it was investigated whether the observed changes in hPPAR{alpha} gene expression are the result of an induction of hPPAR{alpha} gene transcription. Since both CDCA and TCA are specific natural FXR ligands (3, 4, 5), it was furthermore evaluated whether BAs influence hPPAR{alpha} promoter activity via activation of this nuclear receptor. Therefore, a reporter vector driven by a 1.2-kb fragment of the hPPAR{alpha} promoter was transiently transfected into HepG2 cells with or without cotransfected FXR and its heterodimeric partner, RXR, and cells were subsequently treated with CDCA. In HepG2 cells, CDCA alone slightly induced hPPAR{alpha} promoter activity (Fig. 2AGo). Cotransfection of FXR/RXR significantly enhanced CDCA-induced promoter activity to about 3-fold (Fig. 2AGo). Furthermore, in the presence of CDCA, cotransfection with either FXR or RXR alone weakly induced the activity of the 1.2-kb hPPAR{alpha} promoter (Fig. 2BGo). Maximal induction of promoter activity was obtained when both nuclear receptors were cotransfected. Similar BA activation of hPPAR{alpha} promoter activity was observed in the nonhepatic RK13 cell line (Fig. 3AGo). These data indicate that the effect of CDCA on hPPAR{alpha} mRNA levels is exerted, at least in part, at the transcriptional level.



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  		Figure 2. BAs Induce hPPAR{alpha} Promoter Activity

HepG2 cells were transfected with a reporter plasmid driven by the 1.2-kb hPPAR{alpha} promoter in the presence or absence of expression plasmids for FXR and RXR. Data represent the mean ± SD of the luciferase activity normalized to a ß-gal internal transfection control. Relative luciferase activities are shown as fold induction of the activity of the reporter plasmid in the absence of FXR/RXR cotransfection, which was arbitrarily set to 1. Cells were treated with 50 µM CDCA or vehicle (EtOH) (A) or 50 µM CDCA alone (B).

 


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  		Figure 3. A BA-Responsive Region Is Located Between Nucleotides -648 and -536 of the hPPAR{alpha} Promoter

A, RK13 cells were transfected with the indicated hPPAR{alpha} promoter reporter plasmids in the presence or absence of expression plasmids for FXR and RXR. Cells were treated with CDCA (50 µM) or vehicle (EtOH). Data represent the mean ± SD of the luciferase activity normalized to a ß-gal internal transfection control. For each reporter construct, relative luciferase activities are shown as fold induction of the activity of the reporter plasmid in the absence of FXR/RXR cotransfection and CDCA supplementation, which was arbitrarily set to 1. B, HepG2 cells were transfected with the indicated reporter plasmids as described in panel A. Data (mean ± SD) are shown as fold induction of the activity of the nondeleted plasmid in the absence of FXR/RXR cotransfection and CDCA treatment, which was arbitrarily set to 1.

 
The Region between -648 and -536 Nucleotides of the hPPAR{alpha} Promoter Mediates BA Responsiveness
To localize the region within the hPPAR{alpha} promoter that confers transcriptional responsiveness to BAs, serial deletion constructs from -1204 bp to -536 bp of the hPPAR{alpha} promoter were cotransfected with the expression vectors for FXR and RXR in RK13 cells. A marked increase in reporter activity of the largest fragment of the hPPAR{alpha} promoter (-1206/+83) was observed after FXR/RXR cotransfection and treatment with CDCA (50 µM; Fig. 3AGo). Further 5'-deletions between positions -1206 and -648 did not prevent the activation of the reporter gene by BA-activated FXR/RXR. By contrast, deletion of the region between nucleotide (nt) -648 and -536 completely abolished the induction of hPPAR{alpha} promoter activity by CDCA-activated FXR, indicating that this region mediates the effects of BAs on the hPPAR{alpha} promoter. To further demonstrate that the region from nt -648 to nt -536 of the hPPAR{alpha} promoter is entirely responsible for the BA induction, HepG2 cells were cotransfected with a reporter plasmid driven by the hPPAR{alpha} promoter in which the BA-responsive region had been deleted (Fig. 3BGo). Whereas the wild-type promoter was activated by CDCA-activated FXR/RXR, transactivation of the deleted reporter construct was completely abolished. Similar results were obtained in RK13 cells (data not shown). These results demonstrate the importance of the -638/-536 region in the BA regulation of the hPPAR{alpha} promoter.

Identification of a FXRE in the hPPAR{alpha} Gene Promoter
Computer-assisted analysis (46) of the -638/-536 region of the hPPAR{alpha} promoter revealed a degenerated DR5 sequence containing a perfect nuclear receptor half-site (TGACCT). Interestingly, consensus DR5 sites have been previously reported to bind FXR/RXR (9). To determine whether this sequence could be a FXRE, gel shift assays were performed using a radiolabeled oligonucleotide spanning nt -599 to -575 in the presence of in vitro translated FXR and RXR proteins. Both FXR alone or together with RXR were able to bind to the {alpha}FXRE (Fig. 4Go). Furthermore, both FXR and FXR/RXR failed to bind to an oligonucleotide bearing three point mutations in the {alpha}FXRE ({alpha}FXREmut) (Fig. 4Go). The specificity of the receptor-DNA interaction was analyzed by competition studies. Binding of FXR and FXR/RXR was inhibited in a concentration-dependent manner in the presence of increasing concentrations of the unlabeled {alpha}FXRE oligonucleotide (Fig. 5Go, A and B, respectively). Addition of equivalent amounts of unlabeled mutated {alpha}FXRE, however, did not compete for binding of FXR to the labeled wild-type oligonucleotide (Fig. 5Go, A and B). Moreover, both protein complexes could be supershifted by addition of an FXR-specific antibody (Fig. 5Go, A and C), further demonstrating the specificity of the interaction. Finally, competition experiments were performed to determine the relative affinity of FXR/RXR for the novel {alpha}FXRE compared with the previously characterized FXRE from the IBABP promoter. Addition of increasing amounts of unlabeled IBABP-FXRE inhibited the binding of FXR/RXR to the radiolabeled IBABP-FXRE probe in a dose-dependent fashion. Likewise, increasing concentrations of unlabeled {alpha}FXRE were able to compete FXR/RXR binding to the IBABP-FXRE, although complete inhibition could not be achieved. Thus, these results indicate that FXR/RXR binds specifically to the {alpha}FXRE, albeit with lesser affinity compared with the IBABP-FXRE.



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  		Figure 4. Identification of a FXRE in the hPPAR{alpha} Promoter

Autoradiograph of EMSA performed on end-labeled oligonucleotides ({alpha}FXRE or {alpha}FXREmut) using in vitro translated FXR and RXR as described in Materials and Methods.

 


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  		Figure 5. Characterization of the {alpha}FXRE

EMSAs were performed with in vitro translated FXR alone (A) or FXR and RXR (B and C) and the wild-type {alpha}FXRE oligonucleotide probe. Competition experiments were performed in the presence of 100-, 200-, and 400-fold molar excess of the indicated unlabeled oligonucleotides. When indicated, a specific antibody for FXR was added in the binding reaction. SS, Supershifted. D, Autoradiograph of EMSA performed on end-labeled oligonucleotide probe carrying the I-BABP FXRE in the absence or presence of 10-, 50-, 100-, and 200-fold molar excess of either the {alpha}FXRE or I-BABP-FXRE unlabeled oligonucleotides.

 
The FXRE Confers BA Responsiveness to a Heterologous Promoter
To evaluate whether the {alpha}FXRE could confer FXR responsiveness to a heterologous promoter, the {alpha}FXRE was cloned in four copies in front of the thymidine kinase (TK) promoter ({alpha}FXREx4S-TKpGL3), and cotransfection experiments with FXR and RXR expression plasmids were performed in HepG2 cells. CDCA-activated FXR/RXR significantly enhanced the transcriptional activity of this heterologous promoter (Fig. 6AGo). By contrast, a heterologous promoter construct containing three copies of the mutated {alpha}FXRE ({alpha}FXREmutx3S-TKpGL3) failed to be activated by CDCA in the presence of FXR/RXR (Fig. 6AGo).



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  		Figure 6. The hPPAR{alpha} Promoter {alpha}FXRE Confers FXR-Dependent BA Responsiveness to Homo- and Heterologous Promoters

A (right), Schematic representation of the {alpha}FXREx4S-TKpGL3 and {alpha}FXREmutx3S-TKpGL3 constructs; left, HepG2 cells were transfected with the indicated reporter constructs in the presence or absence of cotransfected FXR/RXR. Data are presented as in Fig. 2AGo. B (right), Schematic representation of the indicated reporter plasmids. The bases mutated in p{alpha}(-1206)FXREmut-pGL3 are shown in bold; left, HepG2 cells were transfected with or without FXR/RXR expression plasmids in the presence or absence of CDCA. Data (mean ± SD) are presented as fold induction of the activity of the nonmutated plasmid in the absence of FXR/RXR cotransfection and CDCA treatment, which was arbitrarily set to 1.

 
BA Regulation of the hPPAR{alpha} Promoter Is Dependent on the {alpha}FXRE
To assess whether the {alpha}FXRE is required for the induction of hPPAR{alpha} promoter activity by BAs, HepG2 cells were transfected with the hPPAR{alpha} promoter construct p{alpha}(-1206){alpha}FXREmut-pGL3 in which the {alpha}FXRE was mutated (Fig. 6BGo). In contrast to the wild-type promoter construct p{alpha}(-1206)-pGL3, activity of the mutated promoter was not induced by CDCA-activated FXR/RXR (Fig. 6BGo), thus demonstrating that the BA response of the hPPAR{alpha} promoter occurs via the {alpha}FXRE element.

The Murine PPAR{alpha} Promoter Is Not Responsive to BAs and Does Not Contain a Functional FXRE
Because the effect of BAs on human PPAR{alpha} expression was found to be exerted, at least partially, at the transcriptional level and because PPAR{alpha} mRNA levels are not induced in BA-treated mice, the molecular mechanism behind these species-specific differences in PPAR{alpha} regulation was further studied. Analysis of the murine PPAR{alpha} promoter sequence revealed that the corresponding sequence to the {alpha}FXRE in the mouse gene (m{alpha}FXRE) substantially differs from the human {alpha}FXRE (h{alpha}FXRE) in the 5'-half-site and in the spacing nucleotides (Fig. 7AGo). To test whether these sequence differences render the murine promoter unresponsive to FXR, FXR and RXR expression plasmids were cotransfected with a reporter plasmid containing 1-kb murine PPAR{alpha} promoter, and cells were treated with CDCA or vehicle (EtOH) (Fig. 7BGo). In contrast to the human PPAR{alpha} promoter, the activity of the murine PPAR{alpha} promoter was not influenced by CDCA-activated FXR/RXR. Moreover, activity of a reporter gene driven by three copies of the m{alpha}FXRE cloned in front of the TK promoter (m{alpha}FXREx3S-TKpGL3) was not induced by cotransfected FXR/RXR or by CDCA, contrary to the nearly 4-fold stimulation of an h{alpha}FXRE-driven reporter under identical conditions (Fig. 7CGo). These results are in agreement with in vivo experiments and indicate that mouse PPAR{alpha} transcription is not stimulated by BAs. Furthermore, these experiments show that 5'-half-sites as well as spacing nucleotides are critical for BA activation of the {alpha}FXRE. Thus, the sequence differences between the h{alpha}FXRE and the m{alpha}FXRE may explain the absence of BA responsiveness of the murine PPAR{alpha} promoter and, consequently, the species-specific regulation of PPAR{alpha} expression by BAs.



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  		Figure 7. The Murine PPAR{alpha} Promoter Does Not Contain a Functional FXRE

A, Alignment of human and murine {alpha}FXRE sequences. The numbers are relative to the transcription start site of each promoter. B, HepG2 cells were transfected with reporter plasmids driven by either a 1.2-kb human (p{alpha}(-1206)-pGL3) or 1-kb murine (mp{alpha}(-1000)-pGL3) PPAR{alpha} promoter with or without cotransfected FXR/RXR. Cells were treated with CDCA (50 µM) or vehicle (EtOH) as indicated. Data (mean ± SD) are presented as fold induction of the activity of each reporter in the absence of FXR/RXR cotransfection and CDCA, which was set to 1. C, HepG2 cells transfected with either human {alpha}FXREx4S-TKpGL3 or murine {alpha}FXREx3S-TKpGL3 with or without FXR/RXR expression plasmids in the presence or absence of CDCA (50 µM). Data (mean ± SD) are presented as in panel A.

 
BA Induction of hPPAR{alpha} Gene Expression Enhances the Responsiveness of hPPAR{alpha} Target Genes to hPPAR{alpha} Agonists
To determine the functional relevance of FXR induction of PPAR{alpha} expression, HepG2 cells were treated with CDCA (50 µM) and/or the hPPAR{alpha}-specific agonist GW7647 (250 nM) (47), and mRNA levels of a well characterized hPPAR{alpha} target gene, CPT-I, were measured by real-time PCR. As previously shown (48, 49), CPT-I mRNA levels were induced by approximately 2-fold in cells incubated with GW7647 (Fig. 8Go). Treatment with CDCA also induced CPT-I mRNA levels to a similar extent. Since basal expression levels of CPT-I are regulated by PPAR{alpha} in the absence of added PPAR{alpha} ligand (50), up-regulation of CPT-I gene expression may be due, at least in part, to the increased PPAR{alpha} expression after BA treatment. When cells were incubated with both GW7467 and CDCA, CPT-I gene expression was significantly further enhanced compared with either compound alone. These data suggest that activation of PPAR{alpha} transcriptional activity by its ligand (GW7647) is being further enhanced by the CDCA-induced PPAR{alpha} mRNA levels. Therefore, up-regulation of hPPAR{alpha} expression levels by CDCA positively influences the responsiveness of hPPAR{alpha} target genes to hPPAR{alpha} ligands.



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  		Figure 8. BA Treatment Results in an Enhanced Responsiveness of a PPAR{alpha} Target Gene to PPAR{alpha} Activators

HepG2 cells were incubated with vehicle or CDCA (50 µM) and/or GW7647 (250 nM) for 24 h. Total RNA was extracted and liver CPT-I, and 28S mRNA levels were measured by real-time PCR analysis. Data (mean ± SD) represent liver CPT-I mRNA levels normalized to 28S mRNA with the treated control set as 1.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
MATERIALS AND METHODS
 REFERENCES
 
PPAR{alpha} and FXR are two nuclear receptors that play a major role in metabolic control (25, 51). PPAR{alpha} controls lipid, lipoprotein, and fatty acid metabolism, as well as glucose and energy homeostasis (25). Recently, FXR has also been implicated as a modulator of lipid homeostasis (13, 21, 23). A major function of FXR is to regulate the expression of key enzymes of the BA biosynthetic pathways as well as a number of transporters controlling BA uptake in cells and tissues (13, 14, 15). Interestingly, PPAR{alpha} was also recently shown to influence the expression of a number of enzymes in the BA biosynthetic pathway (37, 38, 39, 42, 43, 44, 52). Thus, PPAR{alpha} and FXR regulate a number of common metabolic pathways, including lipid and BA metabolism. Moreover, these receptors are coexpressed in a number of tissues such as liver, intestine, and kidney. Thus, we hypothesized the existence of a molecular cross-talk between these two nuclear receptor signaling pathways. As a first approach, we investigated whether PPAR{alpha} expression is regulated by BAs.

Our data demonstrate that hPPAR{alpha} mRNA levels are regulated by BAs in human hepatoma cells as well as in human primary hepatocytes. Furthermore, BA treatment induces the activity of the hPPAR{alpha} promoter, suggesting that the increase in PPAR{alpha} expression occurs, at least in part, via transcriptional mechanisms. Using a combination of transient transfection assays and gel shift analysis, a functional FXRE was identified within the hPPAR{alpha} promoter ({alpha}FXRE), which confers BA responsiveness to both homologous and heterologous promoters. Furthermore, a mutation in the {alpha}FXRE abolished BA induction of hPPAR{alpha} promoter activity, indicating that its regulation by BA-activated FXR depends on this element. Moreover, regulation of PPAR{alpha} expression by BAs is controlled in a species-specific manner. Finally, both basal and PPAR{alpha} agonist-induced expression levels of CPT-I, a classical PPAR{alpha} target gene, were up-regulated by CDCA, demonstrating the functional relevance of the BA induction of hPPAR{alpha} expression.

The regulation of hPPAR{alpha} expression by BAs may have several important physiological and pharmacological implications. Fibrate PPAR{alpha} ligands effectively reduce plasma triglyceride levels in humans by a mechanism involving an increase in fatty acid uptake and catabolism resulting in reduced triglyceride and very-low-density lipoprotein production by the liver with a concomitant increase in triglyceride metabolism (27). Thus, PPAR{alpha} is considered to play a key role in controlling triglyceride metabolism. Similarly, BA FXR agonists also influence plasma triglyceride concentrations. Indeed, treatment of rats with the synthetic FXR agonist GW4064 significantly reduced triglyceride levels (22). The mechanisms accounting for this effect have not been identified so far. Moreover, treatment of patients with gallstones with CDCA results in reduced plasma triglyceride levels (53). Finally, treatment of dyslipidemic patients with BA sequestrants, such as cholestyramine, generally results in an elevation of plasma triglycerides (54, 55, 56, 57). Whereas the cholesterol-lowering activity of BA sequestrants is well understood, the triglyceride-elevating mechanisms are presently unclear. BA sequestrants bind BAs in the intestinal lumen and, as such, interrupt their enterohepatic recirculation. As a result, BA sequestrants reduce the pool of BAs, activate BA synthesis from cholesterol, and decrease intestinal cholesterol absorption. These actions on plasma BAs may lead to FXR deactivation and, consequently, to the reduction of FXR-regulated target genes such as PPAR{alpha}. Thus, since FXR agonists induce expression of PPAR{alpha}, which is a major regulator of plasma triglyceride metabolism, it is tempting to speculate that the hypertriglyceridemic actions of these resins are due, at least in part, to lowered FXR activity leading to an abnormal low level of PPAR{alpha} expression and activity. Conversely, the induction of PPAR{alpha} expression may contribute to the triglyceride-lowering activity of FXR agonists in humans (Fig. 9Go). However, since PPAR{alpha} expression is not induced in rodents, the reduction in triglyceride levels observed in these animals treated with an FXR agonist cannot be explained by a PPAR{alpha}-mediated mechanism.



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  		Figure 9. Molecular Cross-Talk between the FXR and PPAR{alpha} Nuclear Receptor Signaling Pathways

BA-activated FXR regulates BA synthesis and transport as well as lipid metabolism. PPAR{alpha} is activated by fatty acids and their derivatives, leading to the regulation of fatty acid and lipoprotein metabolism. The main pathways regulated by each nuclear receptor are depicted by bold arrows. One mechanism identified in this paper is the FXR regulation of fatty acid metabolism via induction of PPAR{alpha} expression.

 
The functional relevance of FXR-induction of PPAR{alpha} is suggested by the demonstration that a well characterized PPAR{alpha} target gene, CPT-I, is induced by BAs. This effect is likely to be mediated, at least in part, via PPAR{alpha}. It is also possible that BA regulation of CPT-I expression is partly mediated directly via FXR, a mechanism that, at present, cannot be ruled out. Nevertheless, BA induction of PPAR{alpha} enhances the responsiveness of CPT-I to PPAR{alpha} ligand treatment. This is consistent with previous reports showing that regulation of PPAR{alpha} expression levels by various stimuli, such as glucocorticoids, stress, and fasting, influences PPAR{alpha} transcriptional activity (50, 58, 59, 60). CPT-I is involved in mitochondrial fatty acid uptake, and this enzyme is believed to be rate limiting for the mitochondrial oxidation of fatty acids. By inducing CPT-I mRNA levels, CDCA is likely to enhance the uptake of fatty acids into mitochondria and their subsequent degradation through ß-oxidation (Fig. 9Go). The cellular amounts of cholesterol and fatty acids increase simultaneously upon uptake of LDL particles in the liver and cholesteryl ester hydrolysis in the lysosomes into their constituent cholesterol and fatty acid moieties. Therefore, regulation of PPAR{alpha} and PPAR{alpha}-mediated pathways, such as fatty acid oxidation by BAs, would represent a mechanism by which cells metabolize cholesterol and oxidize fatty acids in a coordinated manner. Further studies will be required to elucidate whether other steps of the fatty acid oxidation pathway are also modulated by BAs and whether this results in an enhanced fatty acid oxidation.

The induction of PPAR{alpha} by BAs appears to be species specific. Sinal and collaborators (13, 45) examined the expression of PPAR{alpha} in cholic acid-fed wild-type and FXR-deficient mice. PPAR{alpha} expression was influenced by BA treatment neither in wild-type nor in FXR-deficient mice. Our own observations also indicate that PPAR{alpha} mRNA levels are not affected by TCA supplementation in mice. Several aspects of BA and cholesterol metabolism are subject to species-specific regulation. For instance, in rodents, oxysterol-activated liver X receptor-{alpha} stimulates CYP7A1 expression through a liver X receptor response element located in the CYP7A1 promoter, thus inducing cholesterol conversion into BAs (61). However, liver X receptor-{alpha} does not promote human CYP7A1 transcription (62). Thus, induction of BA synthesis by oxysterols occurs only in rodents. Furthermore, molecular defects in human 27-hydroxylase (the rate-limiting enzyme of the acidic BA synthetic pathway), result in cerebrotendinous xanthomatosis, a disorder characterized by reduced BA synthesis, accumulation of tissue cholesterol and cholestanol, and progressive neuropathy (63). However, in mice carrying a null mutation of the sterol 27-hydroxylase gene, no cholestanol accumulation is observed despite a reduction in BA production to about 20% of the normal levels (64). In addition, these mice do not develop the characteristic xanthomas and premature atherosclerotic lesions observed in humans with CYP27 mutations. The regulation of this enzyme is also subject to species variation with CDCA repressing CYP27 mRNA levels in rat hepatocytes, whereas no effects are observed in rabbits and humans (65). Therefore, PPAR{alpha} is another example of a gene the expression of which is regulated in a species-specific manner, being induced by BAs in humans but not in rodents.

The observation that PPAR{alpha} expression is not induced in mice is associated with the absence of BA activation of the murine PPAR{alpha} promoter. This is probably due to the fact that the human {alpha}FXRE is not conserved in the murine promoter, since a reporter driven by the corresponding murine {alpha}FXRE is not responsive to CDCA-activated FXR/RXR. Thus, nucleotide differences between the human and mouse {alpha}FXRE appear to be crucial for BA responsiveness of the PPAR{alpha} promoter. Similarly, subtle differences in the sequence of the CYP7A1 liver X receptor response element between mouse, hamster, and human promoters also explain the species-specific regulation of CYP7A1 gene expression by oxysterols (62).

It was recently reported that BAs may exert antagonistic actions on PPAR{alpha} function (45). The authors showed that BAs interfere with PPAR{alpha} transcriptional activity both in vivo and in vitro. In mice fed a 1% cholic acid diet, BA treatment negatively regulated basal as well as PPAR{alpha} agonist-induced expression of certain PPAR{alpha} target genes encoding peroxisomal ß-oxidation enzymes in a PPAR{alpha}-dependent manner. These data contrast with our results demonstrating an induction of CPT-I expression levels by BAs. This discordance probably results again from species-specific differences in BA metabolism. The studies by Sinal et al. were performed in mice, in which BA regulation of PPAR{alpha} mRNA levels does not take place, or in vitro with a murine PPAR{alpha} expression vector. The PPAR{alpha} target genes analyzed encoded primarily peroxisomal enzymes, which are not regulated by PPAR{alpha} in human hepatocytes (49). Important species-specific differences are further supported by the following: in transient transfection experiments using a hPPAR{alpha} expression vector, BAs failed to antagonize PPAR{alpha} transcriptional activity on a PPAR response element-driven reporter gene (data not shown). Further studies will be required to discern the mechanistic basis for these species differences.

In conclusion, the present study demonstrates that hPPAR{alpha} gene expression is regulated by BAs in a species-specific manner via an FXRE located within the hPPAR{alpha} promoter. In addition, induction of hPPAR{alpha} expression by BAs influences the response of the PPAR{alpha} target gene CPT-I to PPAR{alpha} ligands. This suggests that BAs, in addition to regulating their own synthesis and transport via FXR, also affect fatty acid and lipoprotein metabolism, at least in part, by modulating PPAR{alpha} expression. These observations provide a molecular basis for the physiological cross-talk between the FXR and PPAR{alpha} pathways.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 RESULTS
 DISCUSSION
 MATERIALS AND METHODS
REFERENCES
 
RNA Extraction, RNase Protection, and Northern Blot Analysis
RNA from HepG2 cells and primary hepatocytes was isolated using the Trizol reagent as described by the manufacturer (Life Technologies, Inc., Gaithersburg, MD). The riboprobes specific for hPPAR{alpha} and 36B4 have been previously described (66). Antisense RNA probes were transcribed using the Maxiscript Kit (Ambion, Inc., Austin, TX) using the manufacturer’s protocol. RNase protection analysis was carried out using the Hybspeed RNase protection Kit (Ambion, Inc.) as described (66). Total RNA was isolated from mouse liver by the acid guanidinium thiocyanate/phenol/chloroform method. Northern blot analysis of 10 µg of total RNA was performed exactly as described (67) using a mouse PPAR{alpha} cDNA probe, and the human ribosomal 28S cDNA was used as a control.

Real-Time PCR mRNA Quantification
PPAR{alpha}, CPT-I, and 28S mRNAs were quantified by reverse transcription followed by real-time PCR using a LightCycler (Roche Diagnostics, Meylan, France) as described (68) with oligonucleotide primers specific for hPPAR{alpha} (68) and 28S (69), and hL-CPT-I (5'-ACAGTCGGTGAGGCCTCTTATGAA-3' and 5'-TCTTGCTGCCTGAATGTGAGTTGG-3'). hPPAR{alpha} and hL-CPT-I mRNA levels were normalized to 28S mRNA. PPAR{alpha} and 28S mRNA levels were also quantified on a MX 4000 apparatus (Stratagene, La Jolla, CA) using hPPAR{alpha} (5'-GGTGGACACGGAAAGCCCAC-3' and 5'-GGACCACAGGATAAGTCACC-3') and 28S (69) specific oligonucleotide primers, respectively. PCR amplification was performed employing the Brilliant Quantitative PCR Core Reagent Kit mix as recommended by the manufacturer (Stratagene) and SYBR Green 0.33X (Sigma, L’Isle d’Abeau Chesnes, France). The conditions were 95 C for 10 min, followed by 40 cycles of 30 sec at 95 C, 30 sec at 55 C, and 30 sec at 72 C.

Cloning of Reporter Plasmids
The reporter vectors p{alpha}(-1206)-pGL3, p{alpha}(-648)-pGL3, and p{alpha}(-536)-pGL3 were described previously (68). The reporter construct p{alpha}(-1206){Delta}(-648/-536)-pGL3, in which the region from nt -648 and nt -536 is deleted, was generated by digestion of p{alpha}(--1206)-pGL3 with EcoRI plus PstII, Klenow fill in of cohesive ends, and subsequent ligation. p{alpha}FXREx4S-TKpGL3 and p{alpha}FXREmutx3S-TKpGL3 were created by ligating four or three copies, respectively, of the corresponding double-stranded oligonucleotides ({alpha}FXRE: 5'-GATCCCGGTGTCCCATCGGTGACCTTGGACA-3' for p{alpha}FXREx4S-TKpGL3 and {alpha}FXRE mut: 5'-GATCCCGGTGTCCCATCGGTGATTATGGACA-3' for p{alpha}FXREmutx3S-TKpGL3) in the sense orientation into the BamHI site of TK-pGL3. p{alpha}(-1206)FXREmut-pGL3 was generated by mutating the {alpha}FXRE site using the QuikChange Site-Directed Mutagenesis Kit (Stratagene) and oligonucleotide (5'-GCGGTGTCCCATCGGTGATTATGGACGGTCCCTCCAC-3') and its complementary oligonucleotide according to the manufacturer’s recommendations. Mouse PPAR{alpha} genomic sequences between -1000 and +60 were amplified by PCR using oligonucleotides (5'-GACCGTCCTCGATGCCCTTCAGC-3') and (5'-AACCCTCCAGCCCCCAAAACAGC-3') from a BAC clone containing the 5'-region of the murine PPAR{alpha} gene. The resulting product was cloned into the EcoRV site of pBluescript SK+ (Stratagene) and subsequently cloned into a pGL3 basic plasmid (Promega Corp., Madison, WI) to obtain the reporter vector mp{alpha}(-1000)-pGL3. m{alpha}FXREx3S-TKpGL3 was created by annealing the oligonucleotide (5'-TCTCCCCCGTCGGGTGACCTTGGGCAGTCTCCCCCGTCGGGTGACCTTGGGCAGTCTCCCCCGTCGGGTGACCTTGGGCAG-3'), containing three copies of the murine FXRE, and its complementary before ligation into a SmaI-digested TK-pGL3 reporter vector. All constructs were verified by restriction enzyme digestion and sequence analysis.

Cell Culture And Transient Transfection Assays
Human liver specimens were collected for transplantation at the Moscow Center, and hepatocytes were obtained by a two-step collagenase perfusion as described previously (67). The specimens were obtained from physically healthy donors who died after brain trauma. Permission to use the remaining untransplanted donor liver for scientific research purposes was obtained from the Ministry of Health of the Russian Federation. After 24 h of culture the medium was changed and 100 µM TCA (Sigma, St. Louis, MO) or vehicle was added in serum-free medium for 48 h as previously reported for other target genes (10). HepG2 (human hepatoma) cells were grown on gelatin-coated dishes in DMEM supplemented with 10% fetal calf serum, streptomycin/penicillin, sodium pyruvate, glutamine and nonessential amino acids (Life Technologies, Cergy-Pontoise, France) at 37 C in a humidified 5% CO2 atmosphere. To assess the effect of FXR agonists on mRNA expression, HepG2 cells were incubated in serum-free medium containing the indicated concentrations of CDCA (Sigma) and/or GW7647 (47) for 48 h since maximal induction/repression of FXR has been previously shown to be achieved after 48 h for a number of target genes (10, 11, 21). RK13 (rabbit kidney) and Cos cells were cultured as previously described (66). HepG2 (8 x 104), RK13 (4 x 104), and Cos (4 x 104) cells were transfected using the cationic polymer Exgen 500 (Euromedex, Souffelweyersheim, France) following the manufacturer’s instructions. The indicated pGL3 basic firefly luciferase reporter constructs or of the TK-pGL3 reporters (100 ng) were cotransfected with or without 30–50 ng of pCDNA3-hFXR, and pSG5-murine RXR{alpha}, and 10 ng of the cytomegalovirus-ß-galactosidase (ß-gal) plasmid as internal control. When FXR and murine RXR{alpha} plasmids were not cotransfected, pSG5 (Stratagene) or pcDNA3 (Invitrogen, Leek, The Netherlands) empty vectors were added to the transfection mixture. All DNA mixtures were complemented with pBSK+ plasmid (Stratagene) to a total amount of 500 ng of DNA. After transfection, medium was replaced with fresh medium containing 50 µM CDCA. Luciferase activity was assayed 36 h later, as previously described for other target genes (9, 10, 23), using a LB 9507 LUMAT luminometer. Transfections were carried out in triplicate, and each experiment was repeated at least twice.

Animals and Treatment
Male C57BL/6 mice (IFFA-CREDO, L’Arbresle, France) were divided into two groups of animals (n = 4). One group received a standard rodent chow diet (control), whereas the second group received the same diet containing 0.5% (wt/wt) of TCA (Sigma) for 5 d. At the end of the treatment, animals were killed and liver samples were collected and snap frozen until analyzed.

EMSAs
FXR and RXR{alpha} were synthesized in vitro using the TNT Quick Coupled Transcription/Translation System (Promega Corp.). Double-stranded oligonucleotides were end-labeled with [{gamma}-32P]ATP by using T4-Polynucleotide kinase. Either protein (2.5 µl) was incubated for 15 min at room temperature in a total volume of 20 µl with 2.5 µg poly (dI-dC) and 1 µg herring sperm DNA in binding buffer (10 mM Tris, pH 8.0; 40 mM KCl; 0.05% Nonidet P-40; 6% glycerol; and 1 mM dithiothreitol) before the radiolabeled probe was added. Binding reactions were further incubated for 15 min and resolved by 4% nondenaturing polyacrylamide gel electrophoresis in 0.25x TBE buffer. For competition experiments, the indicated fold excess of unlabeled oligonucleotide [{alpha}FXRE, {alpha}FXREmut, or IBABP-FXRE (19)] over the labeled probe was included in the binding reaction. For supershift experiments, 1 µl of a FXR-specific antibody (SC-1204, Santa Cruz Biotechnology, Inc., Santa Cruz, CA) was added to the binding reaction before addition of the probe.


   ACKNOWLEDGMENTS
 
We thank Christian Duhem, Aline Brechet, and Odile Vidal for their excellent technical assistance. We acknowledge Peter Young (Dupont Merck Pharmaceutical Co., Wilmington, DE), Tim Willson, and Peter Brown (Glaxo Wellcome, Inc., Research Triangle Park, NC) for gifts of different plasmids and the GW7647 agonist. Karine Bertrand and the Chemistry Department of Genfit SA are acknowledged for providing the GW4064 compound.


   FOOTNOTES
 
This work was supported by a grant from the European Community (ERBFMBICT983214; to I.P.T.), a grant from the Association pour la Recherche contre le Cancer (ARC) to C.D., and a grant from FEDER-Conseil Régional Nord Pas-de-Calais (Genopole 01360124; to B.S.).

1 I.P.T. and T.C. contributed equally to this manuscript. Back

2 Current address: Department of Microbiology and the Kaplan Comprehensive Cancer Center, New York University School of Medicine, 550 First Avenue, New York, New York 10016. Back

Abbreviations: BA, Bile acid; CDCA, chenodeoxycholic acid; CPT-I, carnitine palmitoyltransferase I; CYP7A1, cholesterol 7{alpha}-hydroxylase; DR, direct repeat; ER, everted repeat; FXR, farnesoid X receptor; FXRE, FXR response element; ß-gal, ß-galactosidase; hPPAR{alpha}, human PPAR{alpha}; I-BABP, ileal-BA-binding protein; IR, inverted repeat; nt, nucleotide; NTCP, sodium taurocholate transporting polypeptide; PPAR{alpha}, peroxisome proliferator-activated receptor {alpha}; RNase, ribonuclease; RXR, retinoid X receptor; TCA, taurocholic acid; TK, thymidine kinase.

Received for publication March 29, 2002. Accepted for publication November 13, 2002.


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NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  FXRα
Ligands:   GW 7647  |  GW4064



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