Wang Yan-Dong, Chen Wei-Dong, Wang Meihua, Yu Donna, Forman Barry M, Huang Wendong
Department of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Hepatology. 2008 Nov;48(5):1632-43. doi: 10.1002/hep.22519.
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 nuclear factor kappaB (NF-kappaB)-mediated hepatic inflammation. Activation of FXR by its agonist ligands inhibited the expression of inflammatory mediators in response to NF-kappaB activation in both HepG2 cells and primary hepatocytes cultured in vitro. In vivo, compared with wild-type controls, FXR(-/-) mice displayed elevated messenger RNA (mRNA) levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interferon-inducible protein 10, and interferon-gamma in response to lipopolysaccharide (LPS). Examination of FXR(-/-) livers showed massive necroses and inflammation after treatment with LPS at a dose that does not induce significant liver damage or inflammation in wild-type mice. Moreover, transfection of a constitutively active FXR expression construct repressed the iNOS, COX-2, interferon-inducible protein 10 and interferon-gamma mRNA levels induced by LPS administration. FXR activation had no negative effects on NF-kappaB-activated antiapoptotic genes, suggesting that FXR selectively inhibits the NF-kappaB-mediated hepatic inflammatory response but maintains or even enhances the cell survival response. On the other hand, NF-kappaB activation suppressed FXR-mediated gene expression both in vitro and in vivo, indicating a negative crosstalk between the FXR and NF-kappaB 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.
法尼酯X受体（FXR）是一种核受体，通过维持肝脏代谢的稳态在肝脏保护中发挥关键作用。FXR基因敲除小鼠表现出强烈的肝脏炎症，并会自发形成肝肿瘤。在本报告中，我们证明FXR是核因子κB（NF-κB）介导的肝脏炎症的负调节因子。FXR的激动剂配体激活FXR可抑制体外培养的HepG2细胞和原代肝细胞中因NF-κB激活而产生的炎症介质的表达。在体内，与野生型对照相比，FXR（-/-）小鼠在受到脂多糖（LPS）刺激后，诱导型一氧化氮合酶（iNOS）、环氧化酶-2（COX-2）、干扰素诱导蛋白10和干扰素-γ的信使核糖核酸（mRNA）水平升高。对FXR（-/-）小鼠肝脏的检查显示，在用LPS处理后出现大面积坏死和炎症，而相同剂量的LPS在野生型小鼠中不会引起明显的肝损伤或炎症。此外，转染组成型活性FXR表达构建体可抑制LPS给药诱导的iNOS、COX-2、干扰素诱导蛋白10和干扰素-γ的mRNA水平。FXR激活对NF-κB激活的抗凋亡基因没有负面影响，这表明FXR选择性地抑制NF-κB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激活在体外和体内均抑制FXR介导的基因表达，表明FXR和NF-κB信号通路之间存在负反馈调节。我们的研究结果表明，FXR是肝脏炎症的负调节因子，这可能有助于解释FXR在肝脏保护和抑制肝癌发生中的关键作用。
