Hepatic farnesoid X-receptor isoforms α2 and α4 differentially modulate bile salt and lipoprotein metabolism in mice.
Hepatic farnesoid X-receptor isoforms α2 and α4 differentially modulate bile salt and lipoprotein metabolism in mice.
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DOI：
10.1371/journal.pone.0115028
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Groen AK
中科院分区：
文献类型：
--
作者：
Boesjes M;Bloks VW;Hageman J;Bos T;van Dijk TH;Havinga R;Wolters H;Jonker JW;Kuipers F;Groen AK
核受体FXR作为细胞内胆盐传感器，调节胆盐在肠肝循环中的合成和运输。此外，FXR还参与多种关键代谢途径的控制。已知FXR的四种剪接变体，即FXRα1-4。尽管这些异构体在时空表达模式以及转录活性上存在差异，但其生理相关性仍然难以捉摸。我们利用肝脏特异性自互补腺相关病毒载体在全身FXR敲除小鼠中稳定表达这些亚型，从而评估了肝脏FXRα2和FXRα4的特异性作用。FXR敲除小鼠的肝脏基因表达谱在很大程度上被两种同种异型正常化。然而，不同的影响也很明显；FXRα2在降低升高的HDL水平和反抑制肝脏中胆固醇合成调节剂Cyp8b1的表达方面更有效。后者与胆盐池疏水性的改变同时发生。此外，与FXRα4相比，fxr α2的转导导致中性胆固醇排泄量增加，但不影响肠道胆固醇吸收。我们的数据首次表明，肝脏FXRα2和FXRα4对小鼠胆汁盐和脂蛋白代谢具有差异调节作用。
The nuclear receptor FXR acts as an intracellular bile salt sensor that regulates synthesis and transport of bile salts within their enterohepatic circulation. In addition, FXR is involved in control of a variety of crucial metabolic pathways. Four FXR splice variants are known, i.e. FXRα1-4. Although these isoforms show differences in spatial and temporal expression patterns as well as in transcriptional activity, the physiological relevance hereof has remained elusive. We have evaluated specific roles of hepatic FXRα2 and FXRα4 by stably expressing these isoforms using liver-specific self-complementary adeno-associated viral vectors in total body FXR knock-out mice. The hepatic gene expression profile of the FXR knock-out mice was largely normalized by both isoforms. Yet, differential effects were also apparent; FXRα2 was more effective in reducing elevated HDL levels and transrepressed hepatic expression of Cyp8b1, the regulator of cholate synthesis. The latter coincided with a switch in hydrophobicity of the bile salt pool. Furthermore, FXRα2-transduction caused an increased neutral sterol excretion compared to FXRα4 without affecting intestinal cholesterol absorption. Our data show, for the first time, that hepatic FXRα2 and FXRα4 differentially modulate bile salt and lipoprotein metabolism in mice.
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影响因子：
14.9
作者：
del Castillo-Olivares, A;Gil, G
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Gil, G
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