Farnesoid X receptor protects liver cells from apoptosis induced by serum deprivation in vitro and fasting in vivo
Farnesoid X receptor protects liver cells from apoptosis induced by serum deprivation in vitro and fasting in vivo
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DOI：
10.1210/me.2007-0527
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发表时间：
2008-07-01
影响因子：
--
通讯作者：
Huang, Wendong
中科院分区：
文献类型：
--
作者：
Wang, Yan-Dong;Yang, Fan;Huang, Wendong
法尼醇X受体(FXR)是肝脏中的一种关键代谢调节因子，通过维持肝脏代谢产物的动态平衡而发挥作用。最近的研究结果表明，FXR在肝脏生理和病理中可能具有更广泛的功能。在目前的工作中，我们确定了FXR在保护肝细胞免受营养撤除(包括体外血清剥夺或体内饥饿)诱导的凋亡中的新作用。两种FXR配体鹅去氧胆酸(CDCA)和GW4064以剂量依赖的方式从血清剥夺诱导的HepG2细胞中拯救细胞。当FXR被短干扰RNA击倒时，FXR在抑制凋亡方面的这种作用被削弱。免疫印迹结果显示，CDCA和GW4064激活FXR可诱导ERK1/2的磷酸化，而血清剥夺可减弱CDCA和GW4064的作用。在体内，与野生型小鼠相比，FXR-/-小鼠饥饿后肝脏细胞凋亡加剧，磷酸化ERK1/2水平降低。综上所述，我们的研究结果提示FXR在调节肝细胞凋亡方面具有新的作用。
The farnesoid X receptor (FXR) is a key metabolic regulator in the liver by maintaining the homeostasis of liver metabolites. Recent findings suggest that FXR may have a much broader function in liver physiology and pathology. In the present work, we identify a novel role of FXR in protecting liver cell from apoptosis induced by nutritional withdrawal including serum deprivation in vitro or starvation in vivo. Two FXR ligands, chenodeoxycholic acid (CDCA) and GW4064, rescued HepG2 cells from serum deprivation-induced apoptosis in a dose-dependent manner. This effect of FXR on apoptotic suppression was compromised when FXR was knocked down by short interfering RNA. Similarly, the effects of both CDCA and GW4064 were abolished after inhibition of the MAPK pathway by a specific inhibitor of MAPK kinase 1/2. Immunoblotting results indicated that FXR activation by CDCA and GW4064 induced ERK1/2 phosphorylation, which was attenuated by serum deprivation. In vivo, FXR-/- mice exhibited an exacerbated liver apoptosis and lower levels of phosphorylated-ERK1/2 compared to wild-type mice after starvation. In conclusion, our results suggest a novel role of FXR in modulating liver cell apoptosis.