Modulating effect of β-glycyrrhetic acid on the activity of farnesoid X receptor
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Objective: To investigate the modulating effect of β-glycyrrhetic acid(β-GA) on the activity of farnesoid X receptor(FXR).Methods: FXR was transiently transfected into HepG2 cells,and the effect of β-GA on FXR activity was determined.The effect of β-GA on HepG2 cell viability was detected by Celltiter-Glo.The effect of β-GA on FXR target genes was determined by real-time q-PCR.Results: β-GA specifically and does-dependently decreased the activity of FXR induced by CDCA,and selectively down-regulated the expressions of FXR target genes.Conclusion: β-GA can selectively modulate the activity of FXR.Keywords:
Farnesoid X receptor
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Farnesoid X receptor α (FXR) is highly expressed in the liver and regulates the expression of various genes involved in liver repair. In this study, we demonstrated that activated poly(ADP-ribose) polymerase 1 (PARP1) promoted hepatic cell death by inhibiting the expression of FXR-dependent hepatoprotective genes. PARP1 could bind to and poly(ADP-ribosyl)ate FXR. Poly(ADP-ribosyl)ation dissociated FXR from the FXR response element (FXRE), present in the promoters of target genes, and suppressed FXR-mediated gene transcription. Moreover, treatment with a FXR agonist attenuated poly(ADP-ribosyl)ation of FXR and promoted FXR-dependent gene expression. We further established the CCl4-induced acute liver injury model in wild-type and FXR-knockout mice and identified an essential role of FXR poly(ADP-ribosyl)ation in CCl4-induced liver injury. Thus, our results identified poly(ADP-ribosyl)ation of FXR by PARP1 as a key step in oxidative-stress-induced hepatic cell death. The molecular association between PARP1 and FXR provides new insight into the mechanism, suggesting that inhibition of PARP1 could prevent liver injury.
Farnesoid X receptor
PARP1
Small heterodimer partner
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Farnesoid X receptor
Lipogenesis
Troglitazone
Retinoid X receptor
Chromatin immunoprecipitation
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Gluconeogenesis
Farnesoid X receptor
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Farnesoid X receptor (FXR) has been identified as an inhibitor of platelet function and an inducer of fibrinogen protein complex. However, the regulatory mechanism of FXR in hemostatic system remains incompletely understood. In this study, we aimed to investigate the functions of FXR in regulating antithrombin III (AT III). C57BL/6 mice and FXR knockout (FXR KO) mice were treated with or without GW4064 (30 mg/kg per day). FXR activation significantly prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), lowered activity of activated factor X (FXa) and concentrations of thrombin-antithrombin complex (TAT) and activated factor II (FIIa), and increased level of AT III, whereas all of these effects were markedly reversed in FXR KO mice. In vivo, hepatic AT III mRNA and protein expression levels were up-regulated in wild-type mice after FXR activation, but down-regulated in FXR KO mice. In vitro study showed that FXR activation induced, while FXR knockdown inhibited, AT III expression in mouse primary hepatocytes. The luciferase assay and ChIP assay revealed that FXR can bind to the promoter region of AT III gene where FXR activation increased AT III transcription. These results suggest FXR activation inhibits coagulation process via inducing hepatic AT III expression in mice. The present study reveals a new role of FXR in hemostatic homeostasis and indicates that FXR might act as a potential therapeutic target for diseases related to hypercoagulation.
Farnesoid X receptor
Pregnane X receptor
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Aim To investigate expression of farnesoid X receptor(FXR) in murine macrophage cell line ANA-1 and evaluate the effect of FXR agonist chenodexycholic acid(CDCA)on the expression of monocyte chemoattractant protein-1(MCP-1) in ANA-1 cells.Methods ANA-1 cells were cultured and treated with FXR agonist CDCA.The mRNA level of FXR and MCP-1 were detected by reverse transcription-polymerase chain reaction(RT-PCR).Western blot was used to assess the expression of FXR and MCP-1 protein level.Results FXR expressed in ANA-1 cells and acted in an autoregulatory fashion.CDCA significantly reduced MCP-1 mRNA and protein level in ANA-1 cells(P0.05).Conclusions FXR experss in murine macrophage cell line ANA-1.After activated by CDCA,FXR may downregulate MCP-1 directly or indirectly.
Farnesoid X receptor
Monocyte
Chenodeoxycholic acid
Hepatic stellate cell
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Farnesoid X receptor
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The farnesoid X receptor/bile acid receptor (FXR; NR1H4) is a ligand-activated transcription factor that regulates bile acid and lipid homeostasis, and is highly expressed in enterohepatic tissue. FXR is also expressed in vascular tissue. We have investigated whether FXR regulates inflammation and migration in vascular smooth muscle cells.The FXR target gene, small heterodimer partner (SHP), was induced in vascular smooth muscle cells after treatment with synthetic FXR ligands, GW4064, or 6alpha-ethyl-chenodeoxycholic acid. FXR ligands induced smooth muscle cell death and downregulated interleukin (IL)-1beta-induced inducible nitric oxide synthase and cyclooxygenase-2 expression. In addition, FXR ligands suppressed smooth muscle cell migration stimulated by platelet-derived growth factor-BB. Reporter gene assays showed that FXR ligands activated an FXR reporter gene and suppressed IL-1beta-induced nuclear factor (NF)-kappaB activation and iNOS in a manner that required functional FXR and SHP.Our observations suggest that a FXR-SHP pathway may be a novel therapeutic target for vascular inflammation, remodeling, and atherosclerotic plaque stability.
Farnesoid X receptor
Small heterodimer partner
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Abstract The farnesoid X receptor (FXR, NR1H4) belongs to the nuclear receptor superfamily and is activated by bile acids such as chenodeoxycholic acid, or synthetic ligands such as GW4064. FXR is implicated in the regulation of bile acid, lipid, and carbohydrate metabolism. Posttranslational modifications regulating its activity have not been investigated yet. Here, we demonstrate that calcium-dependent protein kinase C (PKC) inhibition impairs ligand-mediated regulation of FXR target genes. Moreover, in a transactivation assay, we show that FXR transcriptional activity is modulated by PKC. Furthermore, phorbol 12-myristate 13-acetate , a PKC activator, induces the phosphorylation of endogenous FXR in HepG2 cells and PKCα phosphorylates in vitro FXR in its DNA-binding domain on S135 and S154. Mutation of S135 and S154 to alanine residues reduces in cell FXR phosphorylation. In contrast to wild-type FXR, mutant FXRS135AS154A displays an impaired PKCα-induced transactivation and a decreased ligand-dependent FXR transactivation. Finally, phosphorylation of FXR by PKC promotes the recruitment of peroxisomal proliferator-activated receptor γ coactivator 1α. In conclusion, these findings show that the phosphorylation of FXR induced by PKCα directly modulates the ability of agonists to activate FXR.
Farnesoid X receptor
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Objective To investigate the effect of farnesoid X receptor(FXR) on the expression of scavenger receptor class B type I and its potential mechanism.Methods Human hepatocyte L02 cells were treated with FXR specific agonist GW4064 and SHP(the specific target gene of FXR)mRNA was detected by RT-PCR;SR-BI mRNA and protein were assayed by using RT-PCR,real time PCR and Western blot.The potential binding site of FXR in the SR-BI promoter region was on line analyzed.Finally,determining the level of PPARγ by RT-PCR.Results The level of SHP mRNA was increased,treated with FXR specific agonist GW4064 with different concentrations for 24h respectively in L02,which demonstrated FXR was functional in L02.SR-BI were raised in both mRNA and protein level after FXR activation.Meanwhile,the level of PPARγ mRNA was inclined by actived FXR.On line analyzing,the classical binding site of FXR in the promoter of SR-BI could not be found.Conclusion FXR could increase the expression of scavenger receptor class B type I in hepatocyte,which might be related to upregulation of PPARγ.
Farnesoid X receptor
Scavenger Receptor
Hepatic stellate cell
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Little is known about transcriptional regulators of UDP-glucuronosyltransferase 2B10 (UGT2B10), an enzyme known to glucuronidate many chemicals and drugs such as nicotine and tricyclic antidepressants. Here, we uncovered that UGT2B10 was transcriptionally regulated by farnesoid X receptor (FXR), the bile acid sensing nuclear receptor. GW4064 and chenodeoxycholic acid (two specific FXR agonists) treatment of HepG2 cells led to a significant increase in the mRNA level of UGT2B10. The treated cells also showed enhanced glucuronidation activities toward amitriptyline (an UGT2B10 probe substrate). In reporter gene assays, the extent of UGT2B10 activation by the FXR agonists was positively correlated with the amount of cotransfected FXR. Consistently, knockdown of FXR by shRNA attenuated the induction effect on UGT2B10 expression. Furthermore, a combination of electrophoretic mobility shift assay and chromatin immunoprecipitation showed that the FXR receptor trans-activated UGT2B10 through its specific binding to the −209- to −197-bp region (an IR1 element) of the UGT2B10 promoter. In summary, our results for the first time established FXR as a transcriptional regulator of human UGT2B10.
Farnesoid X receptor
Glucuronosyltransferase
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