The Hypolipidemic Natural Product Guggulsterone Acts as an Antagonist of the Bile Acid Receptor
Jun Wu1,
Chunsheng Xia1,
Jannika Meier,
Suzhen Li,
Xiao Hu and
Deepak S. Lala
Department of Biotechnology, Pharmacia Corp., St. Louis, Missouri 63198
Address all correspondence and requests for reprints to: Deepak S. Lala, Department of Biotechnology, Mail Zone AA305E, Pharmacia Corp., 700 Chesterfield Parkway North, St. Louis, Missouri 63198. E-mail: deepak.s.lala{at}pharmacia.com.
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ABSTRACT
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Ayurveda, the ancient Indian system of health care and medicine, has a well-organized materia medica in which plants form a dominant part. A key illustration of the exploitation of this knowledge toward the development of a modern drug is the isolation and characterization of two antihyperlipidemic compounds, Z-, and E-guggulsterone from the tree Commiphora mukul, the exudate of which has been traditionally used for mitigating lipid disorders. Here, we demonstrate that Z-guggulsterone and an analog, 80574 currently in clinical trials, act as antagonists of the bile acid receptor (BAR), a member of the intracellular receptor superfamily. These compounds antagonize the activity of BAR in vitro, and in cell culture systems on promoters and endogenous target genes. In biochemical assays, they are able to displace coactivator peptides from the receptor in a dose-dependent manner. The mechanism by which they act as BAR antagonists is likely through their inability to recruit coactivator proteins, failure to release corepressor proteins from unliganded receptor, and ability to compete with BAR agonists to block coactivator recruitment. Our data suggest these compounds may mediate at least some of their effects via the BAR.
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INTRODUCTION
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THE WORD AYURVEDA is derived from Ayus (r), meaning life, and Veda, meaning knowledge; thus, Ayurveda, the ancient Indian system of health care and longevity, literally means the science of life (1, 2). The literature of Ayurveda is vast and was written several centuries ago, with the earliest references dating back to the second millennium BC. A landmark in this field is Sushruta Samitha written by Sushrata, a pioneer of surgery who lived and practiced surgery some 2500 yr ago (1). An interesting paragraph in this ancient text refers to the utility of the exudate (gugglu), a gum resin of the tree Commiphora mukul, in treating obesity and lipid disorders (1). The ethyl acetate extract of this gum resin, designated guggulipid, has since been shown to exhibit lipid-lowering activity in normal and hyperlipidemic rats, rabbits, and monkeys (1, 3, 4). It has also been shown to raise high density lipoprotein levels in rabbits accompanied with a lowering of low density lipoprotein (LDL), to cause regression of atheromatous lesions induced in rabbits on a high fat diet, and it is known to exhibit lipid-lowering effects in humans (5, 6, 7, 8). In 1971, two pregnane derivatives, Z-guggulsterone (2) and E-guggulsterone (1, 2, 9, 10), were identified as the key active ingredients responsible for the hypolipidemic activity of guggulipid. Both isomers of guggulsterone possess similar hypolipidemic activity (1) and an 80:20 mixture of the Z- and E-isomers has been shown to lower cholesterol and triglycerides in normal and high-fat-fed rats (1, 11). Interestingly, guggulsterone and a close analog 80574, currently in clinical trials (1), have also been shown to raise high density lipoprotein in normal rats accompanied with a lowering of very LDL and LDL (1, 2). While these compounds give rise to a very attractive lipid profile in multiple animal models, the precise mechanism by which they function is unclear. This prompted us to search for a potential molecular target that might be responsible for mediating the effects of guggulsterones.
Several nuclear receptors play an important role in regulating fatty acid, cholesterol, and bile acid synthesis, and are critical for the maintenance of lipid homeostasis in vivo (12, 13, 14, 15, 16, 17, 18, 19, 20). These include the bile acid receptor [(BAR)/farnesoid X receptor, NR1H4] (21), liver X receptors (LXRs) (14) and peroxisome proliferator-activated receptors (PPARs) (22), all of which require retinoic X receptor (RXR) as a common partner to recognize and bind to their hormone response elements. Based on this, we examined the possibility that guggulsterones and the compound 80574 might act via some of these nuclear receptors. Here, we show that Z-guggulsterone and 80574 are BAR ligands and act as potent and efficacious BAR antagonists in cell-based assays. They are also efficient at displacing coactivator peptides from agonist bound BAR but are unable to release corepressor molecules from unliganded BAR. In biochemical and cell assays, both compounds weakly antagonize other nuclear receptors but only at high concentrations, indicating selectivity for BAR antagonism. Z-guggulsterone does not have any ability to activate either BAR or any of the other receptors tested, with the exception of the steroid and xenobiotic receptor (SXR). Our data suggest that guggulsterones and analogs may exert at least some of their hypolipidemic effects by antagonizing the BAR.
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RESULTS AND DISCUSSION
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Guggulsterone and 80574 Are BAR Antagonists
The structures of Z- and E-guggulsterone as well as an analog 80574, along with their chemical names, are shown in Fig. 1A
. To test the possibility that guggulsterones and 80574 may function via nuclear receptors, we screened a battery of receptors in both agonist and antagonist mode against these compounds in transient transfection assays, using yeast protein Gal4-nuclear receptor ligand binding domains (LBD) fusions. Both isomers of guggulsterone and 80574 are able to block BAR activity induced in the presence of a synthetic agonist GW4064 (23) by 90% (Fig. 1
, B and C). When tested using varying concentrations of Z-guggulsterone and 80574, both show a dose-dependent repression of the BAR with an IC50 of approximately 15 µM (Fig. 1C
). E-guggulsterone also exhibited a similar dose-response curve (data not shown), we therefore focused our attention on Z-guggulsterone for further experiments. In the same cell-based screen, we also observed that Z-guggulsterone was able to weakly antagonize other receptors including LXRs, PPARs, constitutive androstane receptor, and RXR; however, unlike BAR, maximum repression was approximately 2540%, and occurred at high concentrations (Fig. 1D
). While this indicates selectivity for BAR, it is possible that there is some cross-over of Z-guggulsterone to other nuclear receptors at concentrations equal to or greater than 10 µM, at least in this assay. In the agonist mode, Z-guggulsterone did not show any ability to activate several receptors tested, with the exception of the SXR (Fig. 1E
). Interestingly, 80574, currently in clinical trials, did not activate SXR or any of the other receptors (data not shown), suggesting this molecule may be useful as a hypolipidemic agent but without the potential for inducing CYP3A4, an SXR target gene responsible for metabolism of more than 60% of currently used drugs (24).

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Figure 1. Guggulsterone and 80574 Act as BAR Antagonists
A, Structures of Z-, E-guggulsterone and 80574 with chemical names. B, E-, and Z-guggulsterone antagonize the BAR in transient transfection assays. Gal4-BAR-LBD was transfected with a Gal4 response element-reporter construct and guggulsterone was added in the presence of a BAR agonist (GW4064). Both compounds at 10 µM completely antagonize the induction of BAR by the agonist (60 nM). C, Z-guggulsterone and its analog 80574 exhibit dose-dependent antagonism of the BAR. Increasing amounts of either Z-guggulsterone or 80574 were added to the BAR agonist (60 nM). IC50 in this assay for both compounds is approximately 12 µM. D, Z-guggulsterone is a weak antagonist of other nuclear receptors at high concentrations. A panel of nuclear receptor LBDs as Gal4 fusions were tested in a transfection assay using Huh-7 cells in the presence of selective agonists at their respective EC50s: PPAR , clofibrate; PPAR , cPGI; PPAR , BRL; RXR, LG268; LXR /ß, T0901317; with or without Z-guggulsterone (10 µM). In the case of constitutive androstane receptor, its constitutive activity was tested for antagonism by guggulsterone. Weak antagonism (2545%), of several nuclear receptors is observed at 10 µM Z-guggulsterone. E, Z-guggulsterone is a selective agonist of SXR. A panel of Gal4-nuclear receptor-LBDs was also tested for their ability to be activated by Z-guggulsterone (10 µM). Only the SXR is activated by the compound.
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Z-Guggulsterone and 80574 Act as Selective Ligands for the BAR
Binding of agonists to nuclear receptors has been shown to induce alterations within the LBD leading to conformational changes that allow receptors to interact with coactivator proteins (25). Nuclear receptor antagonists have been shown to displace coactivators by competing with agonists (26). We therefore adapted a biochemical nuclear receptor-coactivator interaction assay to test the ability of guggulsterone to directly compete with a BAR agonist for coactivator recruitment (27). For this, we added a constant amount of GW4064 (60 nM) in the absence or in the presence of increasing amounts of Z-guggulsterone, and 80574. Both Z-guggulsterone and 80574 are effective at blocking coactivator recruitment by the agonist (Fig. 2A
). Other analogs of guggulsterone showed varying degrees of activity in this assay (data not shown). As shown by the full dose-response curve, Z-guggulsterone was able to dissociate the coactivator peptide with an IC50 of approximately 100 nM1 µM (Fig. 2B
). E-guggulsterone was also able to displace coactivator binding in this assay (data not shown). These data demonstrate that both Z-guggulsterone and 80574 act as direct BAR ligands. Because Z-guggulsterone acted as a weak antagonist of other receptors in our cell-based assay, we also tested its ability to displace coactivator peptides from other receptors in the presence of their ligands. As shown (Fig. 2
, C and D), Z-guggulsterone was unable to displace coactivator peptides bound to RXR or LXRß at concentrations up to 1 µM but showed weak displacement at higher concentrations (1050 µM), suggesting Z-guggulsterone may act as a nonselective antagonist of these receptors at such high concentrations. This may not be that unexpected given its simple steroidal structure. However, because antagonism of BAR is observed at much lower concentrations, in both the biochemical and cell assays, Z-guggulsterone clearly exhibits selectivity for the BAR. To provide further evidence that Z-guggulsterone interacts directly with BAR, we carried out a protease protection assay in which its radiolabeled LBD was incubated in the presence or absence of Z-guggulsterone, along with increasing amounts of trypsin. As shown in Fig. 2E
, a protected band was observed only in the presence of Z-guggulsterone, but not in its absence, confirming a direct interaction.

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Figure 2. Z-Guggulsterone and 80574 Act as Selective BAR Ligands
A, Z-guggulsterone and 80574 displace an LxxLL-containing peptide (derived from the coactivator TRAP220) from agonist (GW4064)-bound BAR. The BAR agonist was used at 60 nM. B, Antagonism of the BAR-coactivator peptide interactions by Z-guggulsterone. Coactivator recruitment by GW 4064 (60 nM) was blocked by Z-guggulsterone in a dose-dependent manner with an IC50 of approximately 100 nM1 µM. C, Z-Guggulsterone does not effectively block coactivator interactions with agonist bound RXR. A coactivator peptide optimized for interactions with RXR in the presence of its selective agonist LG268 (28 ) (100 nM), was incubated with different concentrations of Z-guggulsterone. Weak displacement is observed at 10 and 50 µM, suggesting some weak cross-reactivity of the BAR antagonist with RXR at high concentrations. D, Z-Guggulsterone does not effectively block coactivator interactions with agonist bound LXRß. A coactivator peptide optimized for interactions with LXR in the presence of its selective agonist T0901317 (100 nM) (39 ), was incubated with different concentrations of Z-guggulsterone. Weak displacement is observed at 10 and 50 µM, suggesting some cross-reactivity at high concentrations of the BAR antagonist. E, A protease protection assay carried out by incubating 35S-labeled BAR-LBD with trypsin (10 ng/µl), gives rise to a protected band (asterisk) only in the presence of Z-guggulsterone (10 µM), but not in its absence.
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Mechanism of Antagonism by Z-Guggulsterone
To further explore the ability of Z-guggulsterone to compete with agonist-dependent coactivator-receptor interactions, we employed the use of a mammalian two-hybrid assay consisting of a peptide derived from the coactivator TRAP220 fused to the Gal4-DNA binding domain, and a construct in which the BAR-LBD was fused to activation domain factor from viral protein (VP16) (28). As shown, Z-guggulsterone and 80574 were able to block the ability of BAR to interact with the TRAP220 peptide in this assay as well (Fig. 3A
). Because some nuclear receptor antagonists can also possess partial agonist activity, we checked to see whether Z-guggulsterone had any ability to recruit coactivator peptides to the BAR, an indicator of receptor agonism, by itself. No coactivator recruitment was observed even at high concentrations suggesting that this compound does not function as a partial agonist at least in this context (Fig. 3B
). Several nuclear receptors (e.g. retinoic acid receptor, thyroid hormone receptor) are thought to be bound to corepressor proteins [e.g. nuclear receptor corepressor (NCoR)] in the absence of ligand, which are released upon binding to agonists (25). To look for such interactions with the BAR, we used a modified mammalian two-hybrid assay in which the receptor interacting domain of NCoR (25) a corepressor, was fused to the Gal4-DNA binding domain. As with other receptors, the BAR is also bound to NCoR in the absence of ligand, and, GW4064 is fully capable of releasing it, consistent with its role as a BAR agonist (Fig. 3B
). Also, consistent with its role as a BAR antagonist, Z-guggulsterone was unable to effectively release the corepressor domain (Fig. 3B
).

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Figure 3. Mechanism of Antagonism by Z-Guggulsterone
A, Z-Guggulsterone and 80574 block coactivator interactions with BAR in a mammalian two-hybrid assay. A mammalian two-hybrid assay employing the use of a Gal4-LxxLL peptide and a VP-BAR LBD construct was used to test the ability of guggulsterone and analogs to block interactions between the peptide and receptor LBD induced by a BAR agonist. Both 80574 and Z-guggulsterone prevent the interactions in a dose-dependent manner in this cell-based assay. B, Z-guggulsterone does not recruit coactivator peptides to the BAR. Z-guggulsterone was incubated by itself with GST-BAR-LBD to test its ability to recruit the TRAP220 LxxLL peptide. The BAR agonist (GW4064) was used as a positive control. No recruitment is observed in the presence of Z-guggulsterone. C, Z-Guggulsterone is unable to displace NCoR from unliganded BAR. A mammalian two-hybrid assay involving a corepressor NCoR and the BAR-LBD was used to test the ability of Z-guggulsterone to modulate corepressor-receptor interactions. VP-BAR interacts with the corepressor receptor interacting domain in the absence of ligand. In the presence of the BAR agonist (1 µM), the corepressor is released, whereas guggulsterone (10 µM) itself has little effect.
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Collectively, our data suggest that Z-guggulsterone can function as a BAR antagonist through its ability to displace coactivators from agonist-bound BAR, its inability to recruit coactivators by itself, and its inability to fully displace corepressors from unliganded BAR.
Z-Guggulsterone Antagonizes the Induction of BAR Target Genes
Finally, we examined whether Z-guggulsterone could antagonize BAR target genes when activated by its natural ligand chenodeoxycholic acid (CDCA) (21). These include ileal bile-acid binding protein (IBABP), a gene expressed in the gut, which may play an important role in protection of intestinal cells from high concentrations of bile acids (29). An important BAR target gene in the liver is one that encodes small heterodimer partner (SHP) (30), another nuclear receptor that acts as a repressor of yet another member of the intracellular receptor superfamily, liver receptor homolog-1, to down-regulate 7-
-hydroxylase (CYP7A1) the rate-limiting step in conversion of cholesterol to bile acids (31). To test the ability of Z-guggulsterone to down-regulate IBABP, we cloned approximately 600 bp of the mouse promoter upstream of the reporter luciferase, and, transfected human liver cells (Huh-7) that contain endogenous BARs (data not shown). This allows promoter activation by its agonists even in the absence of exogenous receptors. Using this system we tested the ability of Z-guggulsterone to block CDCA-induced IBABP activity. As shown (Fig. 4A
), this is blocked by both Z-guggulsterone and 80574. BAR induction of a multimerized BAR response element (BARRE) derived from the hIBABP promoter was also blocked by both compounds (Fig. 4B
). To demonstrate that endogenous BAR gene induction could be antagonized by guggulsterones, we used HepG2 cells, which also contain endogenous BARs (data not shown) and asked, first, if SHP a target gene in these cells could be induced by CDCA, and second, if Z-guggulsterone could antagonize CDCA induction of cellular SHP gene expression. Although basal SHP levels are high in these cells (data not shown), we observed an approximately 2.5x induction of SHP by CDCA, and this was blocked in a dose-dependent manner when combined with Z-guggulsterone (Fig. 4C
). Induction of ABCA1, a LXR target gene in THP-1 cells, was not blocked by Z-guggulsterone (data not shown). These data clearly demonstrate that Z-guggulsterone is an antagonist of BAR target genes in vitro and in cultured cells.

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Figure 4. Antagonism of BAR Target Genes by Z-Guggulsterone
A, Z-Guggulsterone and 80574 antagonize IBABP promoter activity. The mIBABP promoter was cloned upstream of a luciferase reporter cDNA and transfected into Huh-7 cells. Its natural agonist CDCA was used to activate the promoter using endogenous BAR, either alone, or, in the presence of Z-guggulsterone or 80574. Both BAR antagonists block the ability of CDCA to activate the hIBABP promoter. B, Antagonism by guggulsterone of a BAR activated BARRE derived from the IBABP promoter. The BARRE from the hIBABP promoter was cloned as a multimer (3x) upstream of a minimal promoter-reporter construct and introduced into Huh-7 cells in the presence of CDCA alone, or, with CDCA (100 µM) plus either compound X, Z-guggulsterone or 80574 (each at 10 µM). Both Z-guggul and 80574 antagonize the ability of CDCA to activate the BARRE. C, Z-guggulsterone antagonizes endogenous SHP expression in HepG2 cells. HepG2 cells were treated with CDCA (100 µM); SHP gene induction was measured using quantitative real-time PCR. Endogenous SHP gene induction is completely blocked by Z-guggulsterone.
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The BAR plays a key role in regulating bile acid homeostasis by suppressing CYP7A1 in the liver through SHP activation (13) (23). BAR antagonism would lead to decreased SHP levels, which in turn might be predicted to increase CYP7A1 activity and enhance cholesterol metabolism in vivo, with a net effect of lowering circulating cholesterol levels and increasing excretion of bile acids. Because SHP induction by BAR ligands is antagonized by guggulsterone, this may explain, at least in part, the increase in bile acid secretion and cholesterol lowering properties of these compounds. Full activation of BAR in the liver would be expected to cause repression of CYP7A1, leading to an increase in cholesterol levels (14). From this standpoint, it appears reasonable to think that a BAR antagonist may be useful as a therapeutic agent and this is consistent with some of the effects of guggulsterone. However, it is important to note that other genes important in exporting bile acids from the liver, such as the bile salt excretory pump are also induced by BAR (32) and antagonism of these genes may not be beneficial. Moreover, recent data from BAR knockout animals suggest that complete absence of this key receptor results in a proatherogenic profile and a loss in protection against cholestasis (20), suggesting that activation of BAR may be useful. Thus, at present, it is unclear whether a BAR agonist or antagonist might serve as a useful drug. In addition to its hypolipidemic effects, Guggulsterone also acts as an inhibitor of platelet aggregation (33), stimulates thyroid hormone activity (34, 35), and possesses free radical scavenging properties (36). It is therefore also unclear whether BAR antagonism alone could be responsible for all of the beneficial effects of Z-guggulsterone observed in vivo. It is possible that the weak antagonism of other nuclear receptors at high concentrations of Z-guggulsterone may also contribute to its in vivo pharmacological effects. Another unanswered question is whether Z-guggulsterone acts as an antagonist in all BAR expressing tissues or as a tissue-selective antagonist or even as a partial agonist under specific conditions. For example, bile acid absorbing drugs that act in the intestine, a BAR-expressing tissue, have also been shown to lower LDL cholesterol and improve CYP7A1 activity. Although the mechanisms would be different, it is possible that guggulsterones function as antagonists of BAR pathways selectively in the intestine. Clearly, further experiments designed to understand how antagonism of BAR by these compounds leads to a lowering of lipids in vivo will be important. This would help to clarify the role of this receptor as a therapeutic target and lead to a better understanding of the type of BAR ligands that might be useful in modulating lipid disorders. While additional work needs to be done to decipher the full therapeutic potential of BAR ligands, our findings give further insight into the complex biology of the BAR by raising the intriguing possibility that specific nonsteroidal BAR antagonists may be beneficial in the treatment of hyperlipidemia. It is noteworthy that identification of molecular targets for other biologically active compounds has played an important role in revealing the therapeutic potential of other nuclear receptors, for example, PPARs (37).
In summary, we have shown that Z-guggulsterone, a pregnane derivative from the tree Commiphora mukul, and 80574, act as novel BAR ligands that function as antagonists for the receptor. Our study also highlights the fact that higher plants continue to play a key role in the development of modern drugs and further connects the ancient medical science of Ayurveda to modern molecular pharmacology. Because guggulsterone was identified through a focused effort aimed at developing a modern drug based on Ayurveda (38), it underscores the importance and potential of utilizing a systematic approach in developing drugs from plants with known beneficial properties.
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MATERIALS AND METHODS
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Cell Culture, RNA Isolation, and Transfections
Huh-7 cells were maintained at 37 C in an atmosphere of 5% CO2 in Roswell Park Memorial Institute 1640 medium containing 10% fetal bovine serum. THP-1 cells were grown in Roswell Park Memorial Institute 1640 medium containing 10% fetal bovine serum, 1 mM sodium pyruvate, 50 µM ß-mercaptoethanol, and 10 mM HEPES. For transfections, cells were plated into 96-well plates, and, next day transfected with Gal4-response element-reporter plasmids and Gal4-LBD fusion constructs. Compound was added and cell lysates were assayed for reporter activity after overnight incubation, ß-galactosidase was used for normalization. For transfections using BAR target gene promoters and BARREs, only the reporter linked to either multimerized response elements or the promoter were transfected. Endogenous BARs were used for activation by ligands.
Nuclear Receptor Coactivator Interaction Assays
Biotin-tagged LxxLL-peptides (28) were immobilized on streptavidin-coated 96-well plates in 100 µl of PBS containing 0.05% Tween-20 buffer/well. Glutathione-S-transferase (GST)-nuclear receptor-LBD ± ligand in 100 µl of 10 mM HEPES (pH 7.9), 150 mM NaCl, 2 mM MgCl2, and 5 mM dithiothreitol were added to each well and incubated for 1 h at room temperature. For determination of antagonist activity, tagged LBDs were preincubated with antagonist for 20 min at room temperature before incubating with the agonist. Next, 100 µl of 100 ng/ml Europium-anti-GST antibody were added, incubated for 1 h at room temperature, washed, then 200 µl of enhancement solution (Perkin-Elmer Corp.) was added to each well. Data were collected with a Victor II plate reader (Perkin-Elmer Corp.) in a time-resolved fluorescence mode.
Quantitative Real-Time PCR
Quantitative PCR analysis of SHP gene expression was conducted on the ABI Prism 7700 and 7900 Sequence Detectors. Primer-probe sets were designed using Primer Express 1.5 (ABI, Foster City, CA) and evaluated for their efficiency and linear range using standard curves. RT-PCRs were performed using the ABI One-Step-RT-PCR Kit. Relative expression was determined using the comparative CT method.
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ACKNOWLEDGMENTS
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We thank Dr. Sukh Dev for helpful discussions and also acknowledge the contribution of his laboratory for the first isolation of Z- and E-guggulsterones from guggulipid in 1971. We also thank Drs. Sukh Dev and Nitya Nand for providing the compounds used in this study.
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FOOTNOTES
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1 J. W. and C. X. contributed equally to this work. 
Abbreviations: BAR, Bile acid receptor; BARRE, BAR response element; CDCA, chenodeoxycholic acid; Gal4, yeast protein; GST, glutathione-S-transferase; Huh, human liver cells; IBABP, ileal bile-acid binding protein; LBD, ligand binding domain; LDL, low density lipoprotein; LXR, liver X receptor; NCoR, nuclear receptor corepressor; PPAR, peroxisome proliferator-activated receptor; RXR, retinoic X receptor; SHP, small heterodimer partner; SXR, steroid and xenobiotic receptor; VP16, activation domain factor from viral protein.
Received for publication December 19, 2001.
Accepted for publication April 29, 2002.
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