Farnesoid X receptor expression is reduced in human hepatocellular carcinoma
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Abstract:
Farnesoid X 受体(FXR， NR1H4 ) 是原子荷尔蒙受体总科的一个成员。当然而，他们变老时，以前，研究证明 FXR/ 老鼠自发地得了肝肿瘤的关联到人的 hepatocellular，癌(HCC ) 不清楚。这研究的目的是观察 FXR 表示是否也是在 HCC 的 downregulated 并且在 HCC 讨论减少的 FXR 表示的机制。FXR 和小 heterodimer 搭挡(SHP ) 的表示被即时 PCR 和 immunohistochemical 技术测量。FXR 和它的倡导者活动的表示上的支持 inflammatory cytokines 的效果在主要 hepatocytes 或 HepG2 和 Huh7 房间线被决定。我们的结果证明在人的 HCC 的 FXR 和它的目标基因 SHP 的那表情是强烈与正常的肝纸巾相比的 downregulated。另外，支持 inflammatory cytokines 对由禁止 FXR 倡导者活动的减少 FXR 表示有能力。在结论，这个工作表明 FXR，建议在人的 HCC 开发的 FXR 的一个潜在的角色表示是强烈，在人的 HCC 的 downregulated，它可以被引起由减少了 FXR 倡导者活动。Keywords:
Farnesoid X receptor
Small heterodimer partner
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Farnesoid X receptor
Lipogenesis
Troglitazone
Retinoid X receptor
Chromatin immunoprecipitation
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Farnesoid X receptor (FXR) is a receptor for bile acids and plays an important role in the regulation of bile acid metabolism in the liver. Although FXR has been shown to affect hepatocarcinogenesis through both direct and indirect mechanisms, potential roles of FXR in epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) remain unclear. We examined the effect of several FXR ligands on EMT-related morphological changes in HCC cell lines, such as HuH-7 and Hep3B cells. FXR agonists (chenodeoxycholic acid, GW4064, and obeticholic acid)—but not an antagonist (guggulsterone)—induced actin polymerization and expression of N-cadherin and phosphorylated focal adhesion kinase, although they were less effective than transforming growth factor β (TGF-β). FXR agonist treatment enhanced TGF-β-induced EMT morphologic changes and FXR antagonist inhibited the effect of TGF-β. Thus, FXR activation enhances EMT in HCC and FXR antagonists may be EMT-suppressing drug candidates.
Farnesoid X receptor
Chenodeoxycholic acid
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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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Altered bile acid (BA) signaling is associated with hepatotoxicity. The farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally regulates BA homeostasis. Mice with FXR ablation present hepatocarcinoma (HCC) due to high toxic BA levels. Mice with Abcb4 ablation accumulate toxic BA within the bile ducts and present HCC. We have previously shown that intestinal specific activation of FXR by transgenic VP16-FXR chimera is able to reduce BA pool size and prevent HCC. Here we tested chemical FXR activation by administering for 15 months the dual FXR/ membrane G protein-coupled receptor (TGR5) agonist INT-767 (6α-ethyl-3α,7α,23-trihydroxy-24-nor-5β-cholan-23-sulphate) to Fxr-/- and Abcb4-/- mice. HCC number and size were significantly reduced by INT-767 administration. In contrast, no changes in HCC tumor number and size were observed in Fxr-/- mice fed with or without INT-767. Notably, INT-767 preserved the hepatic parenchyma, improved hepatic function and down-regulated pro-inflammatory cytokines. Moreover, in Abcb4-/- mice INT-767 prevented fibrosis by reducing collagen expression and deposition. Thus, long term activation of FXR is able to reduce BA pool, reprogram BA metabolism and prevent HCC. These data provide the impetus to address the bona fide therapeutic potential of FXR activation in disease with BA-associated development of HCC.
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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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The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that is highly expressed in liver, kidney, adrenals, and intestine. FXR may play an important role in the pathogenesis of cardiovascular diseases via regulating the metabolism and transport of cholesterol. In this study, we report that FXR is also expressed in rat pulmonary artery endothelial cells (EC), a “nonclassical” bile acid target tissue. FXR is functional in EC, as demonstrated by induction of its target genes such as small heterodimer partner (SHP) after treatment with chenodeoxycholic acid, a FXR agonist. Interestingly, activation of FXR in EC led to downregulation of endothelin (ET)-1 expression. Reporter assays showed that activation of FXR inhibited transcriptional activation of the human ET-1 gene promoter and also repressed the activity of a heterologous promoter driven by activator protein (AP)-1 response elements. Electrophoretic mobility-shift and chromatin immunoprecipitation assays indicated that FXR reduced...
Farnesoid X receptor
Small heterodimer partner
Chromatin immunoprecipitation
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Chronic hepatitis B virus infection is a major risk factor for hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) is a hepatitis B virus protein that has multiple cellular functions, but its role in HCC pathogenesis has been controversial. Farnesoid X receptor (FXR) is a nuclear receptor with activities in anti-inflammation and inhibition of hepatocarcinogenesis. However, whether or how FXR can impact hepatitis B virus/HBx-induced hepatocarcinogenesis remains unclear. In this study, we showed that HBx can interact with FXR and function as a coactivator of FXR. Expression of HBx in vivo enhanced FXR-responsive gene regulation. HBx also increased the transcriptional activity of FXR in a luciferase reporter gene assay. The HBx-FXR interaction was confirmed by coimmunoprecipitation and glutathione S-transferase pull-down assays, and the FXR activation function 1 domain was mapped to bind to the third α helix in the C terminus of HBx. We also found that the C-terminally truncated variants of HBx, which were found in clinical HCC, were not effective at transactivating FXR. Interestingly, recruitment of the full-length HBx, but not the C-terminally truncated HBx, enhanced the binding of FXR to its response element. In vivo, FXR ablation markedly sensitized mice to HBx-induced hepatocarcinogenesis.We propose that transactivation of FXR by full-length HBx may represent a protective mechanism to inhibit HCC and that this inhibition may be compromised upon the appearance of C-terminally truncated HBx or when the expression and/or activity of FXR is decreased. (Hepatology 2017;65:893-906).
HBx
Farnesoid X receptor
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Farnesoid X receptor
Small heterodimer partner
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Farnesoid X receptor (FXR, NR1H4) is a member of nuclear hormone receptor superfamily. Previously studies showed that FXR−/− mice spontaneously developed liver tumors when they aged, however, the relevance of which to human hepatocellular carcinoma (HCC) is unclear. The aim of this study is to observe whether FXR expression is also downregulated in HCC and discuss the mechanism of the reduced FXR expression in HCC. Expression of FXR and small heterodimer partner (SHP) was measured by real-time PCR and immunohistochemical technique. Effect of pro-inflammatory cytokines on expression of FXR and its promoter activity were determined in primary hepatocytes or HepG2 and Huh7 cell lines. Our results showed that expression of FXR and its target gene SHP in human HCC was strongly downregulated compared to the normal liver tissues. In addition, pro-inflammatory cytokines were able to decrease FXR expression by inhibiting the FXR promoter activity. In conclusion this work demonstrates FXR expression is strongly downregulated in human HCC, which may be caused by decreased FXR promoter activity, suggesting a potential role of FXR in human HCC development.
Farnesoid X receptor
Small heterodimer partner
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