Parallel regulation of thyroid hormone transporters OATP1c1 and MCT8 during and after endotoxemia at the blood-brain barrier of male rodents.
Parallel regulation of thyroid hormone transporters OATP1c1 and MCT8 during and after endotoxemia at the blood-brain barrier of male rodents.
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DOI：
10.1210/en.2014-1830
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发表时间：
2015-01
期刊：
影响因子：
4.8
通讯作者：
G. Wittmann;Judit Szabon;P. Mohácsik;Shira S Nouriel;B. Gereben;C. Fekete;R. Lechan
中科院分区：
文献类型：
--
作者：
G. Wittmann;Judit Szabon;P. Mohácsik;Shira S Nouriel;B. Gereben;C. Fekete;R. Lechan
越来越多的证据表明，在炎症条件下，由于代谢TH的脱碘酶表达的改变，局部甲状腺激素(TH)的可获得性发生了深刻的变化。然而，炎症是如何通过TH转运蛋白的表达影响TH的可获得性的，这在很大程度上是未知的。在这项研究中，我们研究了细菌脂多糖(LPS)对两种对脑TH稳态至关重要的转运蛋白TH的影响，这两种转运蛋白是有机阴离子转运蛋白1c1(OATP1c1)和单羧酸转运蛋白8(MCT8)。用原位杂交和定量聚合酶链式反应检测大鼠和小鼠前脑中的mRNA水平，并用免疫荧光法检测蛋白水平。内毒素注射后9h，两种转运蛋白的基因表达均显著下降，尤其是脑血管，星形胶质细胞的OATP1c1基因和神经元的MCT8基因表达无明显变化。在内毒素注射后24小时和/或48小时，脑血管中OATP1c1和MCT8的mRNAs显著高于对照组水平。24小时后血管中OATP1c1蛋白水平明显下降，而MCT8蛋白水平无明显下降。这些变化在小鼠和大鼠身上非常相似。这些数据表明，OATP1c1和MCT8的表达在啮齿动物血脑屏障的炎症过程中以平行的方式调节。鉴于这两种转运蛋白在允许TH进入大脑中不可或缺的作用，结果表明，在全身炎症过程中，大脑对TH的摄取减少。
There is increasing evidence that local thyroid hormone (TH) availability changes profoundly in inflammatory conditions due to altered expression of deiodinases that metabolize TH. It is largely unknown, however, how inflammation affects TH availability via the expression of TH transporters. In this study we examined the effect of bacterial lipopolysaccharide (LPS) administration on two TH transporters that are critically important for brain TH homeostasis, organic anion-transporting polypeptide 1c1 (OATP1c1), and monocarboxylate transporter 8 (MCT8). MRNA levels were studied by in situ hybridization and qPCR as well as protein levels by immunofluorescence in both the rat and mouse forebrain. The mRNA of both transporters decreased robustly in the first 9 hours after LPS injection, specifically in brain blood vessels; OATP1c1 mRNA in astrocytes and MCT8 mRNA in neurons remained unchanged. At 24 and/or 48 hours after LPS administration, OATP1c1 and MCT8 mRNAs increased markedly above control levels in brain vessels. OATP1c1 protein decreased markedly in vessels by 24 hours whereas MCT8 protein levels did not decrease significantly. These changes were highly similar in mice and rats. The data demonstrate that OATP1c1 and MCT8 expression are regulated in a parallel manner during inflammation at the blood-brain barrier of rodents. Given the indispensable role of both transporters in allowing TH access to the brain, the results suggest reduced brain TH uptake during systemic inflammation.