Guggulsterone Is a Farnesoid X Receptor Antagonist in Coactivator Association Assays but Acts to Enhance Transcription of Bile Salt Export Pump

Abstract

Guggulipid is an extract of the guggul treeCommiphora mukul and has been widely used to treat hyperlipidemia in humans. The plant sterol guggulsterone (GS) is the active agent in this extract. Recent studies have shown that GS can act as an antagonist ligand for farnesoid X receptor (FXR) and decrease expression of bile acid-activated genes. Here we show that GS, although an FXR antagonist in coactivator association assays, enhances FXR agonist-induced transcription of bile salt export pump (BSEP), a major hepatic bile acid transporter. In HepG2 cells, in the presence of an FXR agonist such as chenodeoxycholate or GW4064, GS enhanced endogenousBSEP expression with a maximum induction of 400–500% that induced by an FXR agonist alone. This enhancement was also readily observed in FXR-dependent BSEP promoter activation using a luciferase reporter construct. In addition, GS alone slightly increased BSEP promoter activation in the absence of an FXR agonist. Consistent with the results in HepG2, guggulipid treatment in Fisher rats increased BSEP mRNA. Interestingly, in these animals expression of the orphan nuclear receptor SHP (small heterodimer partner), a known FXR target, was also significantly increased, whereas expression of other FXR targets including cholesterol 7α-hydroxylase (Cyp 7a1), sterol 12α-hydroxylase (Cyp 8b1), and the intestinal bile acid-binding protein (I-BABP), remained unchanged. Thus, we propose that GS is a selectivebile acid receptormodulator that regulates expression of a subset of FXR targets. Guggulipid treatment in rats lowered serum triglyceride and raised serum high density lipoprotein levels. Taken together, these data suggest that guggulsterone defines a novel class of FXR ligands characterized by antagonist activities in coactivator association assays but with the ability to enhance the action of agonists onBSEP expression in vivo. Guggulipid is an extract of the guggul treeCommiphora mukul and has been widely used to treat hyperlipidemia in humans. The plant sterol guggulsterone (GS) is the active agent in this extract. Recent studies have shown that GS can act as an antagonist ligand for farnesoid X receptor (FXR) and decrease expression of bile acid-activated genes. Here we show that GS, although an FXR antagonist in coactivator association assays, enhances FXR agonist-induced transcription of bile salt export pump (BSEP), a major hepatic bile acid transporter. In HepG2 cells, in the presence of an FXR agonist such as chenodeoxycholate or GW4064, GS enhanced endogenousBSEP expression with a maximum induction of 400–500% that induced by an FXR agonist alone. This enhancement was also readily observed in FXR-dependent BSEP promoter activation using a luciferase reporter construct. In addition, GS alone slightly increased BSEP promoter activation in the absence of an FXR agonist. Consistent with the results in HepG2, guggulipid treatment in Fisher rats increased BSEP mRNA. Interestingly, in these animals expression of the orphan nuclear receptor SHP (small heterodimer partner), a known FXR target, was also significantly increased, whereas expression of other FXR targets including cholesterol 7α-hydroxylase (Cyp 7a1), sterol 12α-hydroxylase (Cyp 8b1), and the intestinal bile acid-binding protein (I-BABP), remained unchanged. Thus, we propose that GS is a selectivebile acid receptormodulator that regulates expression of a subset of FXR targets. Guggulipid treatment in rats lowered serum triglyceride and raised serum high density lipoprotein levels. Taken together, these data suggest that guggulsterone defines a novel class of FXR ligands characterized by antagonist activities in coactivator association assays but with the ability to enhance the action of agonists onBSEP expression in vivo. guggulsterone bile salt export pump farnesoid X receptor chenodeoxycholate cholesterol 7α-hydroxylase intestinal bile acid-binding protein retinoid X receptor α small heterodimer partner steroid receptor coactivator protein-1 selective bile acid receptor modulator fetal bovine serum charcoal-striped fetal bovine serum Dulbecco's modified Eagle's medium glutathioneS-transferase fast protein liquid chromatography triglycerides total cholesterol Guggulipid is an extract of the guggul tree Commiphora mukul and has been widely used to treat hyperlipidemia in humans (1Satyavati G.V. Indian J. Med. Res. 1988; 87: 327-335PubMed Google Scholar, 2Dev S. Environ. Health Perspect. 1999; 107: 783-789Crossref PubMed Scopus (134) Google Scholar). Numerous clinical trials demonstrate that guggulipid effectively lowers serum low density lipoprotein cholesterol and triglyceride levels and increases high density lipoprotein cholesterol levels (3Nityanand S. Srivastava J.S. Asthana O.P. J. Assoc. Physicians India. 1989; 37: 323-328PubMed Google Scholar, 4Singh R.B. Niaz M.A. Ghosh S. Cardiovasc. Drugs Ther. 1994; 8: 659-664Crossref PubMed Scopus (165) Google Scholar). The plant guggulsterones E and Z (stereoisomers) in guggulipid were identified as active ingredients for lipid-lowering (5Beg M. Singhal K.C. Afzaal S. Indian J. Physiol. Pharmacol. 1996; 40: 237-240PubMed Google Scholar). Recent studies have shown that guggulsterone (GS)1 is an antagonist ligand for the farnesoid X receptor (FXR) and inhibited expression of FXR agonist-induced genes (6Urizar N.L. Liverman A.B. Dodds D.T. Silva F.V. Ordentlich P. Yan Y. Gonzalez F.J. Heyman R.A. Mangelsdorf D.J. Moore D.D. Science. 2002; 296: 1703-1706Crossref PubMed Scopus (435) Google Scholar, 7Wu J. Xia C. Meier J. Li S. Hu X. Lala D.S. Mol. Endocrinol. 2002; 16: 1590-1597Crossref PubMed Scopus (138) Google Scholar). It has also been demonstrated that the hepatic lipid-lowering effect of GS was mediated through FXR using FXR knockout mice (6Urizar N.L. Liverman A.B. Dodds D.T. Silva F.V. Ordentlich P. Yan Y. Gonzalez F.J. Heyman R.A. Mangelsdorf D.J. Moore D.D. Science. 2002; 296: 1703-1706Crossref PubMed Scopus (435) Google Scholar). FXR is a nuclear receptor for bile acids and controls expression of critical genes in bile acid and cholesterol homeostasis (8Makishima M. Okamoto A.Y. Repa J.J. Tu H. Learned R.M. Luk A. Hull M.V. Lustig K.D. Mangelsdorf D.J. Shan B. Science. 1999; 284: 1362-1365Crossref PubMed Scopus (2182) Google Scholar, 9Parks D.J. Blanchard S.G. Bledsoe R.K. Chandra G. Consler T.G. Kliewer S.A. Stimmel J.B. Willson T.M. Zavacki A.M. Moore D.D. Lehmann J.M. 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Kerr T.A. Auwerx J. Mangelsdorf D.J. Mol. Cell. 2000; 6: 507-515Abstract Full Text Full Text PDF PubMed Scopus (1232) Google Scholar), sterol 12α-hydroxylase (16Zhang M. Chiang J.Y. J. Biol. Chem. 2001; 276: 41690-41699Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar), the Na+/taurocholate co-transporting polypeptide (17Denson L.A. Sturm E. Echevarria W. Zimmerman T.L. Makishima M. Mangelsdorf D.J. Karpen S.J. Gastroenterology. 2001; 121: 140-147Abstract Full Text PDF PubMed Scopus (373) Google Scholar) and apolipoprotein A-I (18Claudel T. Sturm E. Duez H. Torra I.P. Sirvent A. Kosykh V. Fruchart J.C. Dallongeville J. Hum D.W. Kuipers F. Staels B. J. Clin. Invest. 2002; 109: 961-971Crossref PubMed Scopus (289) Google Scholar), and activates expression of intestinal bile acid-binding protein (I-BABP) (19Grober J. Zaghini I. Fujii H. Jones S.A. Kliewer S.A. Willson T.M. Ono T. Besnard P. J. Biol. Chem. 1999; 274: 29749-29754Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar), phospholipid transfer protein (20Urizar N.L. Dowhan D.H. Moore D.D. J. Biol. Chem. 2000; 275: 39313-39317Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar), bile salt export pump (BSEP) (21Ananthanarayanan M. Balasubramanian N. Makishima M. Mangelsdorf D.J. Suchy F.J. J. Biol. Chem. 2001; 276: 28857-28865Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar, 22Yu J. Lo J.L. Huang L. Zhao A. Metzger E. Adams A. Meinke P.T. Wright S.D. Cui J. J. Biol. Chem. 2002; 277: 31441-31447Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar), dehydroepiandrosterone sulfotransferase (23Song C.S. Echchgadda I. Baek B.S. Ahn S.C. Oh T. Roy A.K. Chatterjee B. J. Biol. Chem. 2001; 276: 42549-42556Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar), and apolipoprotein C-II (24Kast H.R. Nguyen C.M. Sinal C.J. Jones S.A. Laffitte B.A. Reue K. Gonzalez F.J. Willson T.M. Edwards P.A. Mol. Endocrinol. 2001; 15: 1720-1728Crossref PubMed Scopus (224) Google Scholar). BSEP is the major hepatic bile acid transporter that mediates the transport of bile acids across the canalicular membrane (25Lecureur V. Courtois A. Payen L. Verhnet L. Guillouzo A. Fardel O. Toxicology. 2000; 153: 203-219Crossref PubMed Scopus (55) Google Scholar, 26Kullak-Ublick G.A. Stieger B. Hagenbuch B. Meier P.J. Semin. Liver Dis. 2000; 20: 273-292Crossref PubMed Scopus (240) Google Scholar, 27Hofmann A.F. Arch. Intern. Med. 1999; 159: 2647-2658Crossref PubMed Scopus (692) Google Scholar), the rate-limiting step in overall hepatocellular bile salt excretion. BSEP deficiencies in humans result in progressive familial intrahepatic cholestasis type 2 (28Strautnieks S.S. Bull L.N. Knisely A.S. Kocoshis S.A. Dahl N. Arnell H. Sokal E. Dahan K. Childs S. Ling V. Tanner M.S. Kagalwalla A.F. Nemeth A. Pawlowska J. Baker A. Mieli-Vergani G. Freimer N.B. Gardiner R.M. Thompson R.J. Nat. Genet. 1998; 20: 233-238Crossref PubMed Scopus (860) Google Scholar). Recent studies have shown that BSEPtranscription is robustly activated by FXR via an FXR response element in the BSEP promoter (21Ananthanarayanan M. Balasubramanian N. Makishima M. Mangelsdorf D.J. Suchy F.J. J. Biol. Chem. 2001; 276: 28857-28865Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar). To examine the role of GS in regulation of BSEP expression, we evaluated GS in HepG2 cells in combination with an FXR agonist to assess the FXR antagonist activity. To our surprise and in contrast to the FXR antagonist activity reported before, GS enhanced FXR agonist-induced BSEP expression by 400–500% that induced by an FXR agonist alone. A similar pattern of enhancement was also observed in FXR transactivation using a BSEP promoter-driven luciferase reporter construct, indicating that the enhancement ofBSEP expression was mediated by FXR-dependent promoter activation. Consistent with the results in HepG2 cells, guggulipid treatment in rats increased BSEP expression in a dose-dependent manner. In addition, expression of the orphan nuclear receptor SHP (small heterodimer partner), another direct target of FXR B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. Galardi C. Wilson J.G. Lewis M.C. Roth M.E. Maloney P.R. Willson T.M. Kliewer S.A. Mol. Cell. 2000; 6: 517-526Abstract Full Text Full Text PDF PubMed Scopus (1531) Google Scholar, 15Lu T.T. Makishima M. Repa J.J. Schoonjans K. Kerr T.A. Auwerx J. Mangelsdorf D.J. Mol. Cell. 2000; 6: 507-515Abstract Full Text Full Text PDF PubMed Scopus (1232) Google Scholar), was also increased in whereas expression of the other FXR targets including and unchanged. results suggest that GS is a selectivebile acid receptormodulator that regulates expression of a subset of FXR targets. The were of and fetal bovine serum and and for was for and luciferase assays were and guggulsterones Z and E were was The guggulipid with a of was a in for and and and for and were and were and The and were was The Fisher rats were for of total cholesterol and triglycerides were by the of the promoter to the The expression was by the the FXR The of for was by and were J. J. Lo J.L. Huang L. Li Y. J.M. Wright S.D. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). of protein and for a of with the coactivator were J. J. Lo J.L. Huang L. Li Y. J.M. Wright S.D. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The expression and of protein and the as for for antagonist activities FXR in the HepG2 cells, a were in and were in a density of in to were with or for in the of the nuclear was using the and to the of total nuclear were by a was the using the FXR to and the were HepG2 cells were in using the as J. J. Lo J.L. Huang L. Li Y. J.M. Wright S.D. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). for of of of of and of The treatment of cells with FXR assays for and activities were also the as J. J. Lo J.L. Huang L. Li Y. J.M. Wright S.D. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). This was and HepG2 cells were in and of expression by cells were in a density of in and cells were with of in and cells were for was the cells or using the the transcription and were to the was with an increased of the of was used in the of as an was to of BSEP were as of cells of were as of animals and for and BSEP were using the and were by to as and and and and and and and and and for were also rats were with animals in the were a and the treatment were a and of the of the rats were and were by Liver and were for of expression by total cholesterol and triglyceride levels were using the the The used for total cholesterol was and for triglyceride was were the with the assays were for the of were in of with of and for The was to a with of for The was to a and the was to with To a of in was and the was in of The cholesterol was using the and as of cholesterol of of was in of and of was to a of and of of were and by of The was for by for The was to a and of and of were by and as The was and 2 of this was to a of in The were with low and in of The triglyceride was using the and as of triglyceride of To the serum in the treatment was To a of of of and of were The was and a of was to were by the a of were with The cholesterol of was using the It has been reported that GS or E is an FXR antagonist that FXR agonist-induced expression of FXR targets (6Urizar N.L. Liverman A.B. Dodds D.T. Silva F.V. Ordentlich P. Yan Y. Gonzalez F.J. Heyman R.A. Mangelsdorf D.J. Moore D.D. Science. 2002; 296: 1703-1706Crossref PubMed Scopus (435) Google Scholar, 7Wu J. Xia C. Meier J. Li S. Hu X. Lala D.S. Mol. Endocrinol. 2002; 16: 1590-1597Crossref PubMed Scopus (138) Google Scholar). the major bile acid transporter in the is activated by FXR through an FXR response element in the promoter (21Ananthanarayanan M. Balasubramanian N. Makishima M. Mangelsdorf D.J. Suchy F.J. J. Biol. Chem. 2001; 276: 28857-28865Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar). GS also decrease FXR agonist-induced BSEP To this HepG2 cells were with in the presence of the bile acid agonist ligand and BSEP was by alone a for induction of BSEP expression, induced BSEP expression by To our treatment of HepG2 cells with but enhanced the This enhancement was in a GS dose-dependent with a maximum of 400–500% that induced by alone is a and FXR agonist P.R. D.J. A.M. Chandra G. K.D. Moore L.B. Wilson J.G. Lewis M.C. Jones S.A. Willson T.M. J. Med. Chem. 2000; PubMed Scopus Google Scholar). to robustly induced BSEP expression in HepG2 cells with an induction a of J. Lo J.L. Huang L. Zhao A. Metzger E. Adams A. Meinke P.T. Wright S.D. Cui J. J. Biol. Chem. 2002; 277: 31441-31447Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). with in the presence of GW4064, also enhanced in a GS dose-dependent with a maximum of that induced by alone This result that GS can enhance BSEP expression induced by of FXR In the absence of an FXR agonist GS treatment alone significantly BSEP in HepG2 cells HepG2 cells a low of BSEP with a in J. Lo J.L. Huang L. Zhao A. Metzger E. Adams A. Meinke P.T. Wright S.D. Cui J. J. Biol. Chem. 2002; 277: 31441-31447Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). Thus, is that GS alone significantly BSEP or this was small to in this results were with but the Z was used for the studies To the enhancement of endogenousBSEP by GS is a GS was also evaluated in FXR transactivation promoter-driven luciferase In the presence of GW4064, enhanced luciferase activity in a dose-dependent with a that by alone The enhancement BSEP promoter activity was also of with a of shown in 2 enhanced the luciferase activity the of Taken together, these data that GS enhances FXR-dependent BSEP promoter activation in the enhancement of BSEP mRNA. In FXR transactivation with the BSEP treatment of HepG2 cells with alone the absence of an FXR slightly increased luciferase activities in a dose-dependent with a maximum induction of 2 In the treatment alone increased luciferase activities by a maximum of 2 The low of activation onBSEP promoter was mediated through FXR in this expression of the luciferase of an FXR expression In the absence of GS the luciferase activities GS FXR protein was of the to the enhanced BSEP To this HepG2 cells were with GW4064, or GW4064, and FXR protein was by using the acid of the of FXR B.M. E. Chen J. D.J. T. D.J. T. Cell. Full Text PDF PubMed Scopus Google Scholar). This FXR reported by Y. H.R. Edwards P.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). that treatment with significantly FXR with the reported of FXR activities by bile acids in G. Li H. Forman B.M. S. J. A.K. J. J. S. R. L. K. G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). treatment with GS alone significantly FXR protein levels or the FXR that GS has FXR protein levels or with alone is the treatment with the that GS FXR and A FXR coactivator association was used to assess FXR of GS in the This association of FXR with the coactivator J. J. Lo J.L. Huang L. Li Y. J.M. Wright S.D. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). Consistent with the of GS as an FXR antagonist (6Urizar N.L. Liverman A.B. Dodds D.T. Silva F.V. Ordentlich P. Yan Y. Gonzalez F.J. Heyman R.A. Mangelsdorf D.J. Moore D.D. Science. 2002; 296: 1703-1706Crossref PubMed Scopus (435) Google Scholar, 7Wu J. Xia C. Meier J. Li S. Hu X. Lala D.S. Mol. Endocrinol. 2002; 16: 1590-1597Crossref PubMed Scopus (138) Google Scholar), GS the Z or E to FXR In the presence of GS FXR activation with an of and for and Consistent with the these results that GS is an FXR antagonist in the coactivator association To the of GS was to was also using T. M. T. T. M. M. Mol. Endocrinol. 1999; Google Scholar) and R.B. 1999; 20: PubMed Scopus Google Scholar). to the results with GS alone to of the In the presence of GS inhibited FXR activation with an of for and for to that the with a activated FXR in of and with an of and these similar to that using J. Lo J.L. Huang L. Zhao A. Metzger E. Adams A. Meinke P.T. Wright S.D. Cui J. J. Biol. Chem. 2002; 277: 31441-31447Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). data that GS as an FXR antagonist in the coactivator association assays with including and To assess the FXR activity of GS in Fisher rats were with for by animals with a and to and of guggulsterones guggulsterones in the of were for of FXR target expression and for of serum Guggulipid treatment in a dose-dependent in BSEP expression in the with the and guggulipid increased BSEP by and This is with the of GS enhancement of BSEP expression in HepG2 Interestingly, in these animals expression of another FXR target, the orphan nuclear receptor was robustly induced by The induction of also with an of and the of guggulipid The and BSEP was with with the It is known that transcription of and by FXR via an SHP and Interestingly, expression of these genes was by guggulipid expression in rats with in a It has been shown that transcription of in the is robustly by an FXR via an FXR response element in the promoter (19Grober J. Zaghini I. Fujii H. Jones S.A. Kliewer S.A. Willson T.M. Ono T. Besnard P. J. Biol. Chem. 1999; 274: 29749-29754Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar). guggulipid treatment significantly To the results of guggulipid in Fisher another of was also the as that of guggulipid were used and similar results were for expression of the FXR target genes as Taken together, these data suggest that is an agent that regulates a subset of FXR target The serum levels in rats were also Guggulipid effectively serum triglycerides in a dose-dependent with a of and with of and in the and a of and with of and in the cholesterol increased and the and total cholesterol and triglyceride levels in rats with in a and were also in of with guggulipid treatment significantly hepatic whereas the hepatic to significantly increased by and guggulipid of serum that the in total cholesterol was in high density lipoprotein the serum lipoprotein the with and The for high density lipoprotein was significantly increased that of the whereas for low density lipoprotein and low density lipoprotein were by guggulipid results with studies in the R. A.K. Res. 1996; 10: Scopus Google Scholar, S. R. M. Biol. 16: Google Scholar) and also the lipoprotein by guggulipid in humans (3Nityanand S. Srivastava J.S. Asthana O.P. J. Assoc. Physicians India. 1989; 37: 323-328PubMed Google R.B. Niaz M.A. Ghosh S. Cardiovasc. Drugs Ther. 1994; 8: 659-664Crossref PubMed Scopus (165) Google Scholar). In this we demonstrate that GS is an FXR antagonist in coactivator association assays but enhanced FXR expression in cells and in It is that GS as an that regulates expression of a subset of FXR targets in vivo. have to the The is coactivator It is that GS to FXR results in the transcription including of and of To this we have evaluated and in FXR coactivator association GS with of the and the that FXR a subset of to BSEP promoter that by an FXR in the enhanced A is FXR It has been shown that ligand to or receptor in activates target transcription J. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, E. Hu A. J. Biol. Chem. Full Text PDF PubMed Google Scholar, J.C. M.A. C.M. D.S. Y. N. S. A. PubMed Scopus Google Scholar, J.C. S. S. A. 1996; PubMed Scopus Google Scholar). GS treatment in HepG2 FXR in our also the GS treatment in HepG2 the expression of FXR protein levels and that GS treatment significantly FXR protein levels or It has been that FXR expression of and this is mediated by expression that inhibits activity Guggulipid treatment in rats significantly increased expression of in these animals was significantly data the that is by in to SHP L. D. Y. S. C.S. S.S. P. Heyman R.A. M. Moore D.D. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, T.A. S. M. K. S. T. Shan B. D.W. M. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). (6Urizar N.L. Liverman A.B. Dodds D.T. Silva F.V. Ordentlich P. Yan Y. Gonzalez F.J. Heyman R.A. Mangelsdorf D.J. Moore D.D. Science. 2002; 296: 1703-1706Crossref PubMed Scopus (435) Google Scholar) reported that GS treatment hepatic cholesterol in mice with a In our guggulipid increased hepatic cholesterol the increased BSEP expression, in cholesterol and decrease hepatic for this is that were used in the (6Urizar N.L. Liverman A.B. Dodds D.T. Silva F.V. Ordentlich P. Yan Y. Gonzalez F.J. Heyman R.A. Mangelsdorf D.J. Moore D.D. Science. 2002; 296: 1703-1706Crossref PubMed Scopus (435) Google Scholar) used a in GS whereas we used in The Fisher rats with the have a low of hepatic cholesterol to to a with the increased serum cholesterol levels in these The enhanced BSEP expression by GS is FXR In HepG2 cells, enhance expression of the and in the presence of the agonist J. Adams X. N. Jones A.B. J. S. J. G. Wright S.D. J.G. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar) The for enhancement expression of a subset of FXR targets in our GS, an a class of FXR ligands that FXR agonist-induced coactivator in coactivator association assays but enhance FXR target expression in cells and In to GS, other FXR ligands were also observed to have a similar activity as reported for J. J. A. L. and S. the that guggulipid is an agent for treatment of hyperlipidemia in is that an to GS in FXR and a for treatment of and in this including FXR coactivator association to assess FXR antagonist to assess the activities in HepG2 cells by in rats for in serum a for of and for the