The Decrease in Farnesoid X Receptor, Pregnane X Receptor and Constitutive Androstane Receptor in the Liver after Intestinal Ischemia-Reperfusion
The Decrease in Farnesoid X Receptor, Pregnane X Receptor and Constitutive Androstane Receptor in the Liver after Intestinal Ischemia-Reperfusion
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DOI：
10.18433/j38c88
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发表时间：
2012-01-01
影响因子：
2.7
通讯作者：
Iseki, Ken
中科院分区：
文献类型：
--
作者：
Ogura, Jiro;Terada, Yusuke;Iseki, Ken
目的。肠缺血再灌注（I/R）损伤远端器官，包括肝脏，并促进多器官衰竭（MOF）。然而，肠I/R后急性肝损伤的分子机制尚未完全阐明。Farnesoid X受体（FXR）、pregnane X受体（PXR）和constitutive androstane受体（CAR）调节代谢酶和转运体，并协调预防内源性毒性化合物无法适当排泄的肝毒性。在本研究中，我们评估了肠I/R后肝脏中FXR、PXR和CAR的表达水平及其在细胞核中的定位水平。我们还通过体外实验研究了IL-6对FXR、PXR和CAR的表达水平及其在细胞核中的定位水平的影响。方法。我们采用肠I/R模型大鼠。此外，HepG2细胞被用于体外研究。采用Real-time PCR和Western blotting检测mRNA和蛋白表达水平。用核提取物进行Western blotting分析核受体在细胞核中的定位。结果。FXR和PXR表达水平在肠I/R后3 h开始下降，FXR、PXR和CAR表达水平在肠I/R后6 h下降。FXR、PXR和CAR在细胞核中的定位水平在肠I/R后3 h开始下降，在肠I/R后6 h均下降。在HepG2细胞中，IL-6处理24 h后，FXR、PXR和CAR的表达水平分别降低0.5-1 ng/mL、0.5-100 ng/mL和100 ng/mL。IL-6处理24 h后，细胞核中FXR、PXR和CAR的定位水平分别受到0.5 ~ 10 ng/mL、10 ~ 100 ng/mL和10 ~ 100 ng/mL的抑制。结论。肠I/R后肝脏中FXR、PXR和CAR表达水平降低。IL-6是导致这些受体表达减少的主要原因之一。
Purpose. Intestinal ischemia-reperfusion (I/R) damages remote organs, including the liver, and promotes multi-organ failure (MOF). However, the molecular mechanisms underlying acute liver injury after intestinal I/R have not been completely elucidated. Farnesoid X receptor (FXR), pregnane X receptor (PXR) and constitutive androstane receptor (CAR) regulate metabolizing enzymes and transporters, and coordinately prevent hepatotoxicity reflecting an inability of appropriate excretion of endogenous toxic compounds. In this study, we assessed FXR, PXR and CAR expression levels and their localization levels in nuclei in the liver after intestinal I/R. We also investigated the effect of IL-6 on FXR, PXR and CAR expression levels and their localization levels in nuclei in in vitro experiments. Methods. We used intestinal I/R model rats. Moreover, HepG2 cells were used in in vitro study. Real-time PCR and Western blotting were used to assess mRNA and protein expression levels. Nuclear receptor localization in nuclei was analyzed by Western blotting using nuclear extracts. Results. FXR and PXR expression levels began to be decreased at 3 h, and FXR, PXR and CAR expression levels were decreased at 6 h after intestinal I/R. The localization levels of FXR, PXR and CAR in nuclei began to be decreased at 3 h, and all of them were decreased at 6 h after intestinal I/R. In HepG2 cells, FXR, PXR and CAR expression levels were decreased by 0.5-1 ng/mL, 0.5-100 ng/mL and 100 ng/mL IL-6 treatment for 24 h, respectively. FXR, PXR and CAR localization levels in nuclei were suppressed by 0.5-10 ng/mL, 10-100 ng/mL and 10-100 ng/mL IL-6 treatment for 24 h, respectively. Conclusions. FXR, PXR and CAR expression levels are decreased in the liver after intestinal I/R. IL-6 is one of main causes the decreases in expressions of these receptors.