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• W2078751545 abstract "Three genes, fibrinogen-α (FBGα), -β, and -γ, encode proteins that make up the mature FBG protein complex. This complex is secreted from the liver and plays a key role in coagulation in response to vascular disruption. We identified all three FBG genes in a screen designed to isolate genes that are regulated by the farnesoid X receptor (FXR; NR1H4). Treatment of human hepatoma cells with either naturally occurring or synthetic [3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole] FXR ligands resulted in the induction of transcripts for all three genes. The induction of FBGβ mRNA in response to activated FXR appears to be a primary transcriptional response, as it is blocked by actinomycin D but not by cycloheximide. Four FXR isoforms were recently identified that differ either at their N termini and/or by the presence of four amino acids in the hinge region. Interestingly, the activities of the human FBGβ promoter-reporter constructs were highly induced by FXR isoforms that lack the four amino acid insert.The observation that all three FBG subunits are induced by specific FXR isoforms, in response to FXR ligands, suggests that bile acids and FXR modulate fibrinolytic activity. Three genes, fibrinogen-α (FBGα), -β, and -γ, encode proteins that make up the mature FBG protein complex. This complex is secreted from the liver and plays a key role in coagulation in response to vascular disruption. We identified all three FBG genes in a screen designed to isolate genes that are regulated by the farnesoid X receptor (FXR; NR1H4). Treatment of human hepatoma cells with either naturally occurring or synthetic [3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole] FXR ligands resulted in the induction of transcripts for all three genes. The induction of FBGβ mRNA in response to activated FXR appears to be a primary transcriptional response, as it is blocked by actinomycin D but not by cycloheximide. Four FXR isoforms were recently identified that differ either at their N termini and/or by the presence of four amino acids in the hinge region. Interestingly, the activities of the human FBGβ promoter-reporter constructs were highly induced by FXR isoforms that lack the four amino acid insert. The observation that all three FBG subunits are induced by specific FXR isoforms, in response to FXR ligands, suggests that bile acids and FXR modulate fibrinolytic activity. Secretion of fibrinogen (FBG) from hepatocytes into the blood is a key component of the coagulation pathway that ultimately leads to the formation of a fibrous clot in response to vascular disruption (1Koenig W. Fibrin(ogen) in cardiovascular disease: an update.Thromb. Haemost. 2003; 89: 601-609Crossref PubMed Scopus (272) Google Scholar). The mature FBG protein is a hexamer that is formed from disulfide-linked equimolar ratios of three peptides encoded by the FBGα, -β, and -γ genes (2McKee P.A. Rogers L.A. Marler E. Hill R.L. The subunit polypeptides of human fibrinogen.Arch. Biochem. Biophys. 1966; 116: 271-279Crossref PubMed Scopus (91) Google Scholar). FBG expression is restricted almost entirely to the hepatocyte (3Chien K.R. Molecular Basis of Cardiovascular Disease. W. B. Saunders Co., Philadelphia1999Google Scholar). In response to disruption of the vasculature, a signaling cascade originating from either the intrinsic or the extrinsic coagulation pathway leads to the activation of thrombin, which then cleaves small peptides, termed A and B, from the FBG hexamer, allowing fibrin to form (3Chien K.R. Molecular Basis of Cardiovascular Disease. W. B. Saunders Co., Philadelphia1999Google Scholar). Fibrin can self-associate to form filaments that aggregate to form a meshwork of interconnected thick fibers that are a critical component of the clot (3Chien K.R. Molecular Basis of Cardiovascular Disease. W. B. Saunders Co., Philadelphia1999Google Scholar). The activation of thrombin, and thus the production of fibrin, is regulated by a series of enzymes that respond to disruption of the vasculature to initiate the blood coagulation process (3Chien K.R. Molecular Basis of Cardiovascular Disease. W. B. Saunders Co., Philadelphia1999Google Scholar). The production of fibrin is also regulated at the transcriptional level by expression of the FBGα, -β, and -γ genes in the hepatocyte (4Fuller G.M. Zhang Z. Transcriptional control mechanism of fibrinogen gene expression.Ann. NY Acad. Sci. 2001; 936: 469-479Crossref PubMed Scopus (91) Google Scholar). The three FBG genes are clustered in a 65 kb region on human chromosome 4 (5Kant J.A. Fornace Jr., A.J. Saxe D. Simon M.I. McBride O.W. Crabtree G.R.R. Evolution and organization of the fibrinogen locus on chromosome 4: gene duplication accompanied by transposition and inversion.Proc. Natl. Acad. Sci. USA. 1985; 82: 2344-2348Crossref PubMed Scopus (243) Google Scholar, 6Henry I. Uzan G. Weil D. Nicolas H. Kaplan J.C. Marguerie C. Kahn A. Junien C.C. The genes coding for A alpha-, B beta-, and gamma-chains of fibrinogen map to 4q2.Am. J. Hum. Genet. 1984; 36: 760-768PubMed Google Scholar). Hepatic-specific expression is achieved by the requirement for the liver-enriched transcription factor HNF-1 (7Dalmon J. Laurent M. Courtois G. The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element.Mol. Cell. Biol. 1993; 13: 1183-1193Crossref PubMed Google Scholar, 8Courtois G. Morgan J.G. Campbell L.A. Fourel G. Crabtree G.R.R. Interaction of a liver-specific nuclear factor with the fibrinogen and alpha 1-antitrypsin promoters.Science. 1987; 238: 688-692Crossref PubMed Scopus (281) Google Scholar). Expression of the three FBG genes is tightly regulated in a coordinated manner so that the expression of all three genes is induced in response to the same signal (9Otto J.M. Grenett H.E. Fuller G.M. The coordinated regulation of fibrinogen gene transcription by hepatocyte-stimulating factor and dexamethasone.J. Cell Biol. 1987; 105: 1067-1072Crossref PubMed Scopus (71) Google Scholar). Induction of rat and human FBG mRNAs occurs as part of the acute phase response that is activated by interleukin-6 (IL-6) and glucocorticoid signaling pathways (9Otto J.M. Grenett H.E. Fuller G.M. The coordinated regulation of fibrinogen gene transcription by hepatocyte-stimulating factor and dexamethasone.J. Cell Biol. 1987; 105: 1067-1072Crossref PubMed Scopus (71) Google Scholar, 10Mizuguchi J. Hu C.H. Cao Z. Loeb K.R. Chung D.W. Davie E.W.W. Characterization of the 5′-flanking region of the gene for the gamma chain of human fibrinogen.J. Biol. Chem. 1995; 270: 28350-28356Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 11Hu C.H. Harris J.E. Davie E.W. Chung D.W. Characterization of the 5′-flanking region of the gene for the alpha chain of human fibrinogen.J. Biol. Chem. 1995; 270: 28342-28349Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The coordinated regulation of all three FBG genes in response to IL-6 and glucocorticoids is achieved by the presence of distinct transcription factor binding sites flanking each of the three FBG genes rather than through a single common regulatory element (4Fuller G.M. Zhang Z. Transcriptional control mechanism of fibrinogen gene expression.Ann. NY Acad. Sci. 2001; 936: 469-479Crossref PubMed Scopus (91) Google Scholar, 10Mizuguchi J. Hu C.H. Cao Z. Loeb K.R. Chung D.W. Davie E.W.W. Characterization of the 5′-flanking region of the gene for the gamma chain of human fibrinogen.J. Biol. Chem. 1995; 270: 28350-28356Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, 11Hu C.H. Harris J.E. Davie E.W. Chung D.W. Characterization of the 5′-flanking region of the gene for the alpha chain of human fibrinogen.J. Biol. Chem. 1995; 270: 28342-28349Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The farnesoid X receptor (FXR; NRIH4) is a member of a subclass of the nuclear hormone receptor superfamily of transcription factors that form heterodimers with a common partner, the 9-cis retinoid X receptor (RXR). Such transcription factors function by binding to cis-acting response elements located within the promoters, introns or enhancers of their target genes, and regulate gene expression, usually in response to the binding of small lipophilic ligands (12Mangelsdorf D.J. Evans R.M. The RXR heterodimers and orphan receptors.Cell. 1995; 83: 841-850Abstract Full Text PDF PubMed Scopus (2830) Google Scholar). Studies with a limited number of RXR heterodimers suggest that ligands induce a conformational change of the nuclear receptor that promotes the release of corepressor proteins and the subsequent recruitment of coactivator proteins; the net result is increased transcription of the target gene (13Nolte R.T. Wisely G.B. Westin S. Cobb J.E. Lambert M.H. Kurokawa R. Rosenfeld M.G. Willson T.M. Glass C.K. Milburn M.V.V. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma.Nature. 1998; 395: 137-143Crossref PubMed Scopus (1681) Google Scholar, 14Westin S. Kurokawa R. Nolte R.T. Wisely G.B. McInerney E.M. Rose D.W. Milburn M.V. Rosenfeld M.G. Glass C.K.K. Interactions controlling the assembly of nuclear-receptor heterodimers and co-activators.Nature. 1998; 395: 199-202Crossref PubMed Scopus (303) Google Scholar). Differential use of two distinct promoters of the single FXR gene, coupled with alternative mRNA splicing, results in the formation of four FXR isoforms (FXRα1, -α2, -α3, and -α4; originally called FXRα1, -α2, -β1, and -β2) (15Zhang Y. Kast-Woelbern H.R. Edwards P.A. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation.J. Biol. Chem. 2003; 278: 104-110Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 16Huber R.M. Murphy K. Miao B. Link J.R. Cunningham M.R. Rupar M.J. Gunyuzlu P.L. Haws T.F. Kassam A. Powell F. Hollis G.F. Young P.R. Mukherjee R. Burn T.C.C. Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters.Gene. 2002; 290: 35-43Crossref PubMed Scopus (163) Google Scholar). The α1 and α2 isoforms are distinguished from the α3 and α4 isoforms by a truncated N terminus. The FXRα1 and -α3 isoforms contain a four amino acid insert in the hinge region that is absent from both FXRα2 and -α4 (15Zhang Y. Kast-Woelbern H.R. Edwards P.A. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation.J. Biol. Chem. 2003; 278: 104-110Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 16Huber R.M. Murphy K. Miao B. Link J.R. Cunningham M.R. Rupar M.J. Gunyuzlu P.L. Haws T.F. Kassam A. Powell F. Hollis G.F. Young P.R. Mukherjee R. Burn T.C.C. Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters.Gene. 2002; 290: 35-43Crossref PubMed Scopus (163) Google Scholar). The four isoforms differ in their tissue distribution and induce the expression of partially overlapping sets of targets (15Zhang Y. Kast-Woelbern H.R. Edwards P.A. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation.J. Biol. Chem. 2003; 278: 104-110Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 17Anisfeld A.M. Kast-Woelbern H.R. Meyer M.E. Jones S.A. Zhang Y. Williams K.J. Willson T. Edwards P.A.A. Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor.J. Biol. Chem. 2003; 278: 20420-20428Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). In 1999, three groups independently reported that specific bile acids are ligands for human and rat FXR (hFXR and rFXR, respectively) and as such bind to and activate FXR at physiologically relevant concentrations (18Makishima 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.B. Identification of a nuclear receptor for bile acids.Science. 1999; 284: 1362-1365Crossref PubMed Scopus (2144) Google Scholar, 19Parks 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.M. Bile acids: natural ligands for an orphan nuclear receptor.Science. 1999; 284: 1365-1368Crossref PubMed Scopus (1829) Google Scholar, 20Wang H. Chen J. Hollister K. Sowers L.C. Forman B.M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.Mol. Cell. 1999; 3: 543-553Abstract Full Text Full Text PDF PubMed Scopus (1283) Google Scholar). The most potent of these natural ligands is the primary bile acid chenodeoxycholic acid (CDCA) (18Makishima 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.B. Identification of a nuclear receptor for bile acids.Science. 1999; 284: 1362-1365Crossref PubMed Scopus (2144) Google Scholar, 19Parks 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.M. Bile acids: natural ligands for an orphan nuclear receptor.Science. 1999; 284: 1365-1368Crossref PubMed Scopus (1829) Google Scholar, 20Wang H. Chen J. Hollister K. Sowers L.C. Forman B.M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.Mol. Cell. 1999; 3: 543-553Abstract Full Text Full Text PDF PubMed Scopus (1283) Google Scholar). These observations have helped to define a new physiological function for bile acids as metabolically derived regulators of gene expression. High levels of FXR expression are limited to the liver, intestine, kidney, and adrenals, with low levels reported in the stomach, fat, and heart (15Zhang Y. Kast-Woelbern H.R. Edwards P.A. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation.J. Biol. Chem. 2003; 278: 104-110Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar, 16Huber R.M. Murphy K. Miao B. Link J.R. Cunningham M.R. Rupar M.J. Gunyuzlu P.L. Haws T.F. Kassam A. Powell F. Hollis G.F. Young P.R. Mukherjee R. Burn T.C.C. Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters.Gene. 2002; 290: 35-43Crossref PubMed Scopus (163) Google Scholar, 21Sinal C.J. Tohkin M. Miyata M. Ward J.M. Lambert G. Gonzalez F.J.J. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.Cell. 2000; 102: 731-744Abstract Full Text Full Text PDF PubMed Scopus (1409) Google Scholar). However, with the exception of the intestinally expressed ileal bile acid binding protein (I-BABP) gene, all other FXR target genes reported to date were identified from analysis of hepatic tissue or cells (22Edwards P.A. Kast H.R. Anisfeld A.M. BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis.J. Lipid Res. 2002; 43: 2-12Abstract Full Text Full Text PDF PubMed Google Scholar). Hepatic FXR target genes fall into a limited number of groups. One group, which includes the ABC transporters BSEP (21Sinal C.J. Tohkin M. Miyata M. Ward J.M. Lambert G. Gonzalez F.J.J. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.Cell. 2000; 102: 731-744Abstract Full Text Full Text PDF PubMed Scopus (1409) Google Scholar, 23Ananthanarayanan M. Balasubramanian N. Makishima M. Mangelsdorf D.J. Suchy F.J.J. Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor.J. Biol. Chem. 2001; 276: 28857-28865Abstract Full Text Full Text PDF PubMed Scopus (650) Google Scholar), multidrug resistance-associated protein 2 (MRP2) (24Kast H.R. Goodwin B. Tarr P.T. Jones S.A. Anisfeld A.M. Stoltz C.M. Tontonoz P. Kliewer S. Willson T.M. Edwards P.A.A. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor.J. Biol. Chem. 2002; 277: 2908-2915Abstract Full Text Full Text PDF PubMed Scopus (772) Google Scholar), multidrug resistance protein, MDR3 (human) (25Huang L. Zhao A. Lew J.L. Zhang T. Hrywna Y. Thompson J.R. Pedro N. de Royo I. Blevins R.A. Pelaez F. Wright S.D. Cui J.J. Farnesoid X receptor activates transcription of the phospholipid pump MDR3.J. Biol. Chem. 2003; 278: 51085-51090Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar), and rodent Mdr2 (26Liu Y. Binz J. Numerick M.J. Dennis S. Luo G. Desai B. MacKenzie K.I. Mansfield T.A. Kliewer S.A. Goodwin B. Jones S.A.A. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis.J. Clin. Invest. 2003; 112: 1678-1687Crossref PubMed Scopus (354) Google Scholar), together with the fibroblast growth factor-19 (27Holt J.A. Luo G. Billin A.N. Bisi J. McNeill Y.Y. Kozarsky K.F. Donahee M. Wang Y. da Mansfield T.A. Kliewer S.A. Goodwin B. Jones S.A.A. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis.Genes Dev. 2003; 17: 1581-1591Crossref PubMed Scopus (532) Google Scholar) and the small heterodimeric partner (SHP) (28Goodwin 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.A. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.Mol. Cell. 2000; 6: 517-526Abstract Full Text Full Text PDF PubMed Scopus (1500) Google Scholar, 29Kerr T.A. Saeki S. Schneider M. Schaefer K. Berdy S. Redder T. Shan B. Russell D.W. Schwarz M.M. Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis.Dev. Cell. 2002; 2: 713-720Abstract Full Text Full Text PDF PubMed Scopus (290) Google Scholar, 30Wang L. Lee Y.K. Bundman D. Han Y. Thevananther S. Kim C.S. Chua S.S. Wei P. Heyman R.A. Karin M. Moore D.D.D. Redundant pathways for negative feedback regulation of bile acid production.Dev. Cell. 2002; 2: 721-731Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar, 31Lu T.T. Makishima M. Repa J.J. Schoonjans K. Kerr T.A. Auwerx J. Mangelsdorf D.J.J. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors.Mol. Cell. 2000; 6: 507-515Abstract Full Text Full Text PDF PubMed Scopus (1216) Google Scholar), functions to decrease hepatic bile acid concentrations by increasing export and decreasing bile acid synthesis. A second group of FXR target genes encode proteins that influence lipoprotein levels in the serum and decrease plasma triglycerides (17Anisfeld A.M. Kast-Woelbern H.R. Meyer M.E. Jones S.A. Zhang Y. Williams K.J. Willson T. Edwards P.A.A. Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor.J. Biol. Chem. 2003; 278: 20420-20428Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 22Edwards P.A. Kast H.R. Anisfeld A.M. BAREing it all: the adoption of LXR and FXR and their roles in lipid homeostasis.J. Lipid Res. 2002; 43: 2-12Abstract Full Text Full Text PDF PubMed Google Scholar, 28Goodwin 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.A. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.Mol. Cell. 2000; 6: 517-526Abstract Full Text Full Text PDF PubMed Scopus (1500) Google Scholar, 32Watanabe M. Houten S.M. Wang L. Moschetta A. Mangelsdorf D.J. Heyman R.A. Moore D.D. Auwerx J.J. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c.J. Clin. Invest. 2004; 113: 1408-1418Crossref PubMed Scopus (971) Google Scholar, 33Zhang Y. Castellani L.W. Sinal C.J. Gonzalez F.J. Edwards P.A.A. Peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR.Genes Dev. 2004; 18: 157-169Crossref PubMed Scopus (295) Google Scholar, 34Claudel T. Inoue Y. Barbier O. Duran-Sandoval D. Kosykh V. Fruchart J. Fruchart J.C. Gonzalez F.J. Staels B.B. Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression.Gastroenterology. 2003; 125: 544-555Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar, 35Sirvent A. Claudel T. Martin G. Brozek J. Kosykh V. Darteil R. Hum D.W. Fruchart J.C. Staels B.B. The farnesoid X receptor induces very low density lipoprotein receptor gene expression.FEBS Lett. 2004; 566: 173-177Crossref PubMed Scopus (85) Google Scholar). The identification of this latter group of FXR target genes may help explain the molecular mechanism underlying the observations that administration of chenodeoxycholate to humans resulted in decreased plasma triglyceride levels (36Bell G.D. Lewis B. Petrie A. Dowling R.H. Serum lipids in cholelithiasis: effect of chenodeoxycholic acid therapy.BMJ. 1973; 3: 520-523Crossref PubMed Scopus (64) Google Scholar). Activated FXR also has a hepatoprotective role (26Liu Y. Binz J. Numerick M.J. Dennis S. Luo G. Desai B. MacKenzie K.I. Mansfield T.A. Kliewer S.A. Goodwin B. Jones S.A.A. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis.J. Clin. Invest. 2003; 112: 1678-1687Crossref PubMed Scopus (354) Google Scholar, 37Wagner M. Fickert P. Zollner G. Fuchsbichler A. Silbert D. Tsybrovskyy O. Zatloukal K. Guo G.L. Schuetz J.D. Gonzalez F.J. Marschall H.U. Denk H. Trauner M.M. Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice.Gastroenterology. 2003; 125: 825-838Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar) and regulates genes involved in gluconeogenesis (38Yamagata K. Daitoku H. Shimamoto Y. Matsuzaki H. Hirota K. Ishida J. Fukamizu A.A. Bile acids regulate gluconeogenic gene expression via small heterodimer partner-mediated repression of hepatocyte nuclear factor 4 and Foxo1.J. Biol. Chem. 2004; 279: 23158-23165Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar). In a recent report, FXR was also shown to induce the human kininogen gene, suggesting a role in anticoagulation (39Zhao A. Lew J.L. Huang L. Yu J. Zhang T. Hrywna Y. Thompson J.R. Pedro N. de Blevins R.A. Pelaez F. Wright S.D. Cui J.J. Human kininogen gene is transactivated by the farnesoid X receptor.J. Biol. Chem. 2003; 278: 28765-28770Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). In addition, the microarray data reported by Downes et al. (40Downes M. Verdecia M.A. Roecker A.J. Hughes R. Hogenesch J.B. Kast-Woelbern H.R. Bowman M.E. Ferrer J.L. Anisfeld A.M. Edwards P.A. Rosenfeld J.M. Alvarez J.G. Noel J.P. Nicolaou K.C. Evans R.M.M. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR.Mol. Cell. 2003; 11: 1079-1092Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar) suggest that there may be numerous other hepatic FXR target genes that modulate diverse biochemical pathways still to be elucidated. Surprisingly, the latter microarray data also suggest that three structurally unrelated FXR ligands, CDCA, 3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chloro-stilben-4-yl)-oxymethyl-5-isopropyl-isoxazole (GW4064), and fexaramine, regulate distinct subsets of hepatic genes (40Downes M. Verdecia M.A. Roecker A.J. Hughes R. Hogenesch J.B. Kast-Woelbern H.R. Bowman M.E. Ferrer J.L. Anisfeld A.M. Edwards P.A. Rosenfeld J.M. Alvarez J.G. Noel J.P. Nicolaou K.C. Evans R.M.M. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR.Mol. Cell. 2003; 11: 1079-1092Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar). In an effort to identify new FXR target genes and define new signaling pathways by which bile acids influence gene expression in the hepatocyte, we performed a microarray-based screen of RNA populations from HepG2 hepatoma cells that overexpress FXR and compared expression profiles from cells that were treated with FXR agonists or vehicle. Here, we report the identification of three novel FXR targets (FBGα, -β, and -γ). These data suggest an unexpected link between bile acid signaling and fibrinolytic activity, and this represents a new paradigm for bile acid function. GW4064 and LG100153, a synthetic RXR agonist, were gifts from Dr. Patrick Maloney (GlaxoSmithKline) (41Maloney P.R. Parks D.J. Haffner C.D. Fivush A.M. Chandra G. Plunket K.D. Creech K.L. Moore L.B. Wilson J.G. Lewis M.C. Jones S.A. Willson T.M.M. Identification of a chemical tool for the orphan nuclear receptor FXR.J. Med. Chem. 2000; 43: 2971-2974Crossref PubMed Scopus (457) Google Scholar) and Dr. Richard Heyman (Ligand Pharmaceuticals) (42Kast 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.A. Activated FXR induces apoC-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids.Mol. Endocrinol. 2001; 15: 1720-1728Crossref PubMed Scopus (0) Google Scholar), respectively. The retroviral vector MSCV-IRES-Neo was a gift from Dr. Owen Witte (UCLA). Mammalian expression vectors for rFXR (pCMX-rFXR) and human RXRα (pCMX-hRXRα) were gifts from Dr. Ron Evans (Salk Institute, La Jolla, CA). Mammalian expression vectors for murine FXR (pCMX-mFXRα1, -α2, -α3, and -α4) have been described (in earlier publications, FXRα3 and -α4 were termed FXRβ1 and -β2, respectively) (15Zhang Y. Kast-Woelbern H.R. Edwards P.A. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation.J. Biol. Chem. 2003; 278: 104-110Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar). Cycloheximide and actinomycin D were purchased from Sigma. The sources of other reagents have been noted elsewhere (24Kast H.R. Goodwin B. Tarr P.T. Jones S.A. Anisfeld A.M. Stoltz C.M. Tontonoz P. Kliewer S. Willson T.M. Edwards P.A.A. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor.J. Biol. Chem. 2002; 277: 2908-2915Abstract Full Text Full Text PDF PubMed Scopus (772) Google Scholar). The generation and maintenance of HepG2 and stably infected HepG2-rFXR or HepG2-Neo cells have been described (42Kast 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.A. Activated FXR induces apoC-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids.Mol. Endocrinol. 2001; 15: 1720-1728Crossref PubMed Scopus (0) Google Scholar). HuH7 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum. CV-1 cells were maintained as described (15Zhang Y. Kast-Woelbern H.R. Edwards P.A. Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation.J. Biol. Chem. 2003; 278: 104-110Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar). Unless otherwise indicated, HepG2 and HuH7 cells were cultured in medium containing superstripped FBS for 24 h before the addition of ligands or Me2SO (vehicle) for an additional 8–24 h. Total RNA was isolated using TRIzol reagent and was resolved (5–10 μg/lane) on a 1% agarose, 2.2 M formaldehyde gel, transferred to a nylon membrane (Hybond N+; Amersham Biosciences, Inc.), and cross-linked to the membrane with ultraviolet light. cDNA probes were radiolabeled with [32P]dCTP using the Rediprime™ II labeling kit (Amersham Biosciences, Inc.). Membranes were hybridized using the QuikHyb hybridization solution (Stratagene, La Jolla, CA) according to the manufacturer's protocol. Blots were normalized for variations of RNA loading by hybridization to a control probe, either 18S ribosomal cDNA or the ribosomal protein 36B4. The RNA levels were quantitated using a PhosphorImager (ImageQuant software; Molecular Dynamics, Inc., Sunnyvale, CA). The promoters for the human FBGβ gene were amplified from the human bacterial artificial chromosome clone RPCI11-21G22 and cloned into the KpnI/Nhe I sites of the pGL3 vector (Promega). The FBGβ −2500/+1 construct was amplified using the 5′ primer 5′-ACACGGTACCACATGATAATATTCTTTG and the 3′ primer 5′-ACACGCTAGCCCATCCTTTTCATGTAGACT. Additional constructs used the same 3′ primer and internal 5′ primers. All constructs were sequenced before transfection and shown to contain wild-type sequence. HepG2 cells were transiently transfected using the modified bovine serum (MBS) mammalian transfection kit (Stratagene), with minor modifications. HepG2 cells, on 48-well plates, were transiently transfected with a reporter plasmid (100 ng) and 50 ng of pCMX-rFXR, pCMX-mFXRα1, pCMX-mFXRα2, pCMX-mFXRα3, pCMX-mFXRα4, or VP16-hFXR together with 5 ng of pCMX-hRXRα and 50 ng of pCMV-β-galactosidase, as indicated in the figure legends. After 3.5 h, the cells were treated with 10% superstripped FBS and one of the following ligands: CDCA, LG100153 (a synthetic RXR agonist), or GW4064. The cells were lysed, and the luciferase activities were normalized to β-galactosidase activity (24Kast H.R. Goodwin B. Tarr P.T. Jones S.A. Anisfeld A.M. Stoltz C.M. Tontonoz P. Kliewer S. Willson T.M. Edwards P.A.A. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor.J. Biol. Chem. 2002; 277: 2908-2915Abstract Full Text Full Text PDF PubMed Scopus (772) Google Scholar). All transfections were performed in triplicate, and similar results were obtained in at least three independent experiments. As detailed in previous reports (24Kast H.R. Goodwin B. Tarr P.T. Jones S.A. Anisfeld A.M. Stoltz C.M. Tontonoz P. Kliewer S. Willson T.M. Edwards P.A.A" @default.
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• W2078751545 title "Activation of the nuclear receptor FXR induces fibrinogen expression: a new role for bile acid signaling" @default.
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