Perello Mario, Friedman Theodore, Paez-Espinosa Veronica, Shen Xiaoxiong, Stuart Ronald C, Nillni Eduardo A
Division of Endocrinology, Department of Medicine Brown University/Rhode Island Hospital, Providence, Rhode Island 02903, USA.
Endocrinology. 2006 Jun;147(6):2705-16. doi: 10.1210/en.2005-1609. Epub 2006 Feb 23.
Over the last few years, our laboratory has demonstrated that different physiological conditions or stressors affect the posttranslational processing of hypophysiotropic and nonhypophysiotropic proTRH and, consequently, the output of TRH and other proTRH-derived peptides. These alterations in proTRH processing are generally associated with parallel changes in the levels of two members of the family of prohormone convertases 1/3 and 2 (PC1/3 and PC2). An important regulator of proTRH is thyroid hormone, which is the peripheral end product of the hypothalamic (TRH)-pituitary (TSH)-thyroid (T3/4) (HPT) axis. In this study we investigated the effect of thyroid status on the processing of proTRH inside and outside the HPT axis. Our data showed that high levels of thyroid hormone down-regulated PC1/3 and PC2 and TRH synthesis, which led to an accumulation of intermediate forms of proTRH processing. Conversely, low levels of thyroid hormone up-regulated proTRH synthesis and PC1/3 and PC2 levels. Control of the activity of PCs and proTRH processing occurred specifically in the paraventricular nucleus, whereas no change due to thyroid status was found in the lateral hypothalamus or preoptic area. The posttranslational regulation of proTRH processing in the paraventricular nucleus by thyroid status is a novel aspect of the regulation of the HPT axis, which may have important implications for the pathophysiology of hypo- and hyperthyroidism.
在过去几年中，我们实验室已证明，不同的生理状况或应激源会影响促甲状腺激素释放激素原（proTRH）和非促甲状腺激素释放激素原的翻译后加工过程，进而影响促甲状腺激素释放激素（TRH）及其他源自proTRH的肽类的输出。proTRH加工过程中的这些改变通常与激素原转化酶1/3和2家族（PC1/3和PC2）两个成员水平的平行变化相关。proTRH的一个重要调节因子是甲状腺激素，它是下丘脑（TRH）-垂体（促甲状腺激素，TSH）-甲状腺（T3/4）（HPT）轴的外周终产物。在本研究中，我们调查了甲状腺状态对HPT轴内外proTRH加工过程的影响。我们的数据显示，高水平的甲状腺激素会下调PC1/3和PC2以及TRH的合成，这导致proTRH加工中间形式的积累。相反，低水平的甲状腺激素会上调proTRH的合成以及PC1/3和PC2的水平。PCs活性及proTRH加工过程的调控特异性地发生在室旁核，而下丘脑外侧区或视前区未发现因甲状腺状态改变而产生的变化。甲状腺状态对室旁核中proTRH加工的翻译后调控是HPT轴调控的一个新方面，可能对甲状腺功能减退和亢进的病理生理学具有重要意义。
