Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response.
Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response.
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DOI：
10.1002/hep.22519
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发表时间：
2008-11
期刊：
影响因子：
13.5
通讯作者：
Huang, Wendong
中科院分区：
文献类型：
--
作者：
Wang, Yan-Dong;Chen, Wei-Dong;Wang, Meihua;Yu, Donna;Forman, Barry M.;Huang, Wendong
法尼醇X受体（FXR）是一种核受体，通过维持肝脏代谢的稳态在肝保护中起关键作用。FXR敲除小鼠表现出强烈的肝脏炎症，并发生自发性肝脏肿瘤。在这份报告中，我们证明了FXR是NF-κ B介导的肝脏炎症的负调节剂。在体外培养的HepG 2细胞和原代肝细胞中，FXR激动剂配体激活FXR可抑制NF-κB激活引起的炎症介质的表达。在体内，与野生型对照组相比，FXR−/−小鼠表现出诱导型一氧化氮合酶（iNOS）、环氧合酶-2（考克斯-2）、干扰素-γ诱导蛋白10（IP-10）和干扰素-γ（IFN-γ）的mRNA水平升高，以响应脂多糖（LPS）。FXR−/−肝脏的检查显示，在用LPS治疗后，在野生型小鼠中不会引起显著的肝损伤和炎症的剂量下，出现大量坏死和炎症。此外，转染组成型活性FXR表达构建体抑制LPS给药诱导的iNOS、考克斯-2、IP-10和IFN-γ mRNA水平。FXR激活对NF-κ B激活的抗凋亡基因没有负面影响，表明FXR选择性抑制NF-κ B介导的肝脏炎症反应，但维持甚至增强细胞存活反应。另一方面，NF-κB激活抑制了体内外FXR介导的基因表达，表明FXR和NF-κB信号通路之间存在负串扰。我们的研究结果表明，FXR是肝脏炎症的负性介质，这可能有助于FXR在肝脏保护和抑制肝癌发生中的关键作用。
The farnesoid X receptor (FXR) is a nuclear receptor that plays key roles in hepatoprotection by maintaining the homeostasis of liver metabolism. FXR null mice display strong hepatic inflammation and develop spontaneous liver tumors. In this report, we demonstrate that FXR is a negative modulator of NF-κB-mediated hepatic inflammation. Activation of FXR by its agonist ligands inhibited the expression of inflammatory mediators in response to the NF-κB activation in both HepG2 cells and primary hepatocytes cultured in vitro. In vivo, compared to the wild-type controls, FXR−/−mice displayed elevated mRNA levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interferon-γ-inducible protein 10 (IP-10), and interferon-γ (IFN-γ) in response to lipopolysacchride (LPS). Examination of FXR−/− livers showed massive necroses and inflammation after treatment with LPS at a dose that does not induce significant liver damage and inflammation in wild-type mice. Moreover, transfection of a constitutively active FXR expression construct repressed the iNOS, COX-2, IP-10 and IFN-γ mRNA levels induced by LPS administration. FXR activation had no negative effects on NF-κB-activated anti-apoptotic genes, suggesting that FXR selectively inhibits the NF-κB-mediated hepatic inflammatory response but maintains or even enhances the cell survival response. On the other hand, NF-κB activation suppressed FXR-mediated gene expression both in vitro and in vivo, indicating a negative crosstalk between the FXR and NF-κB signaling pathways. Our findings reveal that FXR is a negative mediator of hepatic inflammation, which may contribute to the critical roles of FXR in hepatoprotection and suppression of hepatocarcinogenesis.
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