參與下丘腦-垂體-甲狀腺軸負(fù)反饋調(diào)控的分子元件研究進(jìn)展

左衛(wèi)星, 張志飛, 劉志民, 王超群

1.中國人民解放軍第五四六醫(yī)院, 烏魯木齊 841700；2.濰坊醫(yī)學(xué)院臨床醫(yī)學(xué)院, 山東 濰坊 261053；3.第二軍醫(yī)大學(xué)附屬長征醫(yī)院, 上海 200003；4.第二軍醫(yī)大學(xué)附屬長海醫(yī)院, 上海 200433

參與下丘腦-垂體-甲狀腺軸負(fù)反饋調(diào)控的分子元件研究進(jìn)展

左衛(wèi)星1, 張志飛2, 劉志民3*, 王超群4*

1.中國人民解放軍第五四六醫(yī)院, 烏魯木齊 841700；2.濰坊醫(yī)學(xué)院臨床醫(yī)學(xué)院, 山東 濰坊 261053；3.第二軍醫(yī)大學(xué)附屬長征醫(yī)院, 上海 200003；4.第二軍醫(yī)大學(xué)附屬長海醫(yī)院, 上海 200433

下丘腦-垂體-甲狀腺(hypothalamic-pituitary-thyroid，HPT)軸負(fù)反饋調(diào)節(jié)是維持血清甲狀腺激素(thyroid hormone,TH)水平穩(wěn)定的最重要的機(jī)制。目前，普遍認(rèn)為位于下丘腦室旁核(paraventricular nuclei,PVN)的促垂體區(qū)的促甲狀腺激素釋放激素(thyrotropin-releasing hormone,TRH)神經(jīng)元是HPT軸的核心調(diào)節(jié)區(qū)域。研究認(rèn)為在血液循環(huán)中，不僅三碘甲狀腺原氨酸(T3)參與HPT軸的負(fù)反饋調(diào)節(jié)，甲狀腺素(T4)也可通過中樞神經(jīng)系統(tǒng)伸長細(xì)胞的脫碘酶2(Dio2)催化脫碘來影響細(xì)胞中T3的可用性，從而參與其中。促垂體區(qū)的TRH神經(jīng)元通過甲狀腺激素轉(zhuǎn)運(yùn)體攝取循環(huán)中的TH，而TH進(jìn)入PVN的TRH神經(jīng)元或垂體促甲狀腺區(qū)細(xì)胞核與甲狀腺激素受體(TRs)(特別是TRβ2)結(jié)合后，可招募輔因子，共同參與相應(yīng)靶基因的調(diào)控。此外，中樞神經(jīng)系統(tǒng)伸長細(xì)胞表達(dá)的焦谷氨酰肽酶Ⅱ(PPⅡ)可降解釋放的TRH，從而影響不同甲狀腺功能狀態(tài)下到達(dá)垂體門靜脈的TRH水平。綜述了參與HPT軸調(diào)節(jié)的分子元件，以期為甲狀腺功能或甲狀腺軸異常疾病的科學(xué)研究及臨床治療提供參考。

HPT軸；負(fù)反饋；甲狀腺激素；脫碘酶

反饋調(diào)節(jié)是生命系統(tǒng)中非常普遍的調(diào)節(jié)機(jī)制，它對于機(jī)體維持穩(wěn)態(tài)具有重要意義。在下丘腦-垂體-甲狀腺軸中，血液循環(huán)中的甲狀腺激素水平變化能反饋調(diào)節(jié)下丘腦釋放的TRH和腺垂體分泌的促甲狀腺激素(thyroid stimulating hormone,TSH)，其涉及的信號通路精密而準(zhǔn)確，因此，探究HPT軸調(diào)控的分子通路有助于明確下丘腦-垂體-甲狀腺軸的中樞調(diào)控機(jī)制，可為臨床上治療甲狀腺功能異?；蚣谞钕佥S異常疾病提供理論基礎(chǔ)。雖然HPT軸的反饋調(diào)節(jié)現(xiàn)象早已被發(fā)現(xiàn)，但其分子機(jī)制的研究仍在不斷推進(jìn)。故本文將對參與HPT軸中樞負(fù)反饋調(diào)控的重要信號分子(包括促甲狀腺激素釋放激素、脫碘酶、甲狀腺激素轉(zhuǎn)運(yùn)體、甲狀腺激素受體、輔因子、焦谷氨酰肽酶Ⅱ)進(jìn)行綜述，以期為相關(guān)研究提供參考。

1 HPT軸中樞調(diào)控模式概述

下丘腦室旁核(PVN)促垂體區(qū)的TRH神經(jīng)元是分泌TRH的主要部位(圖1)。先前的研究發(fā)現(xiàn)人的TRH基因的啟動子區(qū)有3個負(fù)向甲狀腺激素反應(yīng)元件(TREs)，而甲狀腺激素受體(TRs)能夠以單體、同二聚體、異二聚體的形式與TREs結(jié)合，進(jìn)而介導(dǎo)甲狀腺激素對TRH靶基因的負(fù)反饋調(diào)控作用[1]。但HPT軸的調(diào)節(jié)不僅與循環(huán)中的TH水平相關(guān)，還需要多種分子的共同參與才能使循環(huán)中的TH進(jìn)入中樞神經(jīng)系統(tǒng)發(fā)揮調(diào)控作用。首先，甲狀腺激素是由核受體介導(dǎo)發(fā)揮生物學(xué)效應(yīng)的激素，甲狀腺激素必須通過甲狀腺激素轉(zhuǎn)運(yùn)體穿過血-腦和血-腦脊液屏障最終進(jìn)入TRH神經(jīng)元細(xì)胞核內(nèi)才能發(fā)揮其調(diào)控作用。進(jìn)入細(xì)胞后，其不同活性形式的三碘甲狀腺原氨酸(T3)、甲狀腺素(T4)相互轉(zhuǎn)化受細(xì)胞(如伸長細(xì)胞)內(nèi)脫碘酶(Dio)的調(diào)控。進(jìn)入TRH神經(jīng)元細(xì)胞核后，與大多數(shù)核受體一樣，甲狀腺激素對基因的轉(zhuǎn)錄調(diào)控還依賴于甲狀腺激素受體及輔因子的參與。另外，伸長細(xì)胞表達(dá)的焦谷氨酰肽酶Ⅱ(PPⅡ)能降解釋放的TRH，從而影響不同甲狀腺功能狀態(tài)下到達(dá)垂體門靜脈的TRH水平[2]。

2 參與HPT軸反饋調(diào)控的分子元件

參與HPT軸反饋調(diào)控的分子元件包括促甲狀腺激素釋放激素、脫碘酶、甲狀腺激素轉(zhuǎn)運(yùn)體、甲狀腺激素受體、輔因子、焦谷氨酰肽酶Ⅱ(表1)。

2.1 促甲狀腺激素釋放激素

下丘腦室旁核(PVN)的TRH神經(jīng)元被認(rèn)為是HPT軸的核心調(diào)節(jié)區(qū)域[3～5]。早有證據(jù)表明這些神經(jīng)元的缺失會嚴(yán)重?fù)p害TSH分泌的調(diào)節(jié)[6]，即TRH在決定TSH生物活性中起著至關(guān)重要的作用[7～9]。成熟TRH是一種源自促甲狀腺激素釋放激素前體(pro-TRH)經(jīng)激素原轉(zhuǎn)化酶加工而來的三肽，通過正中隆起分泌到達(dá)垂體，刺激TSH的合成和釋放。TRH的轉(zhuǎn)錄[10,11]和翻譯后處理[12]均能被T3所抑制。對下丘腦促垂體區(qū)TRH神經(jīng)元的負(fù)反饋調(diào)節(jié)是保證循環(huán)中甲狀腺激素水平穩(wěn)定的重要調(diào)節(jié)機(jī)制[11]。當(dāng)循環(huán)中甲狀腺激素水平升高時，TRH基因表達(dá)下降；而甲狀腺功能減退時，TRH基因表達(dá)增加[13]。研究表明甲狀腺激素對TRH轉(zhuǎn)錄的調(diào)節(jié)相對迅速，在外源性甲狀腺激素給藥后5 h內(nèi)即可抑制PVN區(qū)TRH基因的轉(zhuǎn)錄[10]。Nikrodhanond等[8]的研究發(fā)現(xiàn)，TRβ敲除小鼠的TH和TSH水平顯著升高，而雙敲除(TRβ、TRH均被敲除)小鼠比TRβ敲除小鼠顯示出更低的TH和TSH水平，并且只有雙敲除小鼠經(jīng)丙硫氧嘧啶(PTU)處理35 d后，其TSH不能反饋性升高。該研究表明TRH對TSH和TH的合成均很重要，在HPT軸的調(diào)節(jié)中占據(jù)主導(dǎo)地位。但在甲狀腺功能嚴(yán)重減退、TRH較低時，垂體依然能夠促進(jìn)TSH的合成[8,14]，說明TH除了在TRH神經(jīng)元水平上發(fā)生負(fù)反饋作用，還會在TSH的水平上進(jìn)行調(diào)節(jié)。

圖1 HPT軸中樞調(diào)控分子模式圖Fig.1 Molecular pattern of central modulation in HPT axis.

表1 參與HPT軸反饋調(diào)控的分子元件的比較Table 1 Comparison of related molecular components involved in HPT axis feedback regulation.

2.2 脫碘酶

早期研究認(rèn)為在循環(huán)中只有T3水平可影響HPT軸的負(fù)反饋調(diào)節(jié)，但Kakucska等[15]發(fā)現(xiàn)甲減大鼠循環(huán)中的T3水平恢復(fù)正常而不干預(yù)T4時，下丘腦PVN的TRH mRNA并未恢復(fù)正常。只有循環(huán)中的T3水平嚴(yán)重高于正常值時，TRH mRNA的表達(dá)才降到正常范圍內(nèi)[16]。由此，研究者認(rèn)為循環(huán)中T4在中樞神經(jīng)系統(tǒng)中轉(zhuǎn)化為T3是參與反饋調(diào)節(jié)機(jī)制的一個重要環(huán)節(jié)。甲狀腺激素(TH)的激活或滅活是通過脫碘酶脫碘實現(xiàn)的。脫碘酶(Dio)包括3型，其中Dio1、Dio2主要催化外環(huán)碘的脫碘作用，使T4轉(zhuǎn)化為活性更強(qiáng)的T3；而Dio3只能對內(nèi)環(huán)碘脫碘，使T3、T4失活為T2和rT3。中樞神經(jīng)系統(tǒng)主要表達(dá)Dio2和Dio3，其中，Dio2主要在漏斗核和正中隆突的神經(jīng)膠質(zhì)細(xì)胞及第三腦室細(xì)胞中表達(dá)，而Dio3主要存在于室旁核、視上核和漏斗核。

脫碘酶能影響腦組織細(xì)胞內(nèi)T3的可用性[17]，腦組織中的T4在Dio2催化下轉(zhuǎn)換成活性更強(qiáng)的T3。Dio2缺乏時，盡管循環(huán)中T3水平正常，但下丘腦中T3含量會減少[17]，因此在下丘腦中發(fā)揮作用的T3至少部分是從局部T4通過脫碘酶轉(zhuǎn)換而來的。而下丘腦脫碘酶主要在伸長細(xì)胞(tanycytes)中表達(dá)[18, 19]。伸長細(xì)胞是位于第三腦室底部腹側(cè)壁和正中隆起處室管膜上的特殊膠質(zhì)細(xì)胞，是血和腦脊液之間的選擇性雙向轉(zhuǎn)運(yùn)通路。目前認(rèn)為伸長細(xì)胞中的Dio2對HPT軸的動態(tài)平衡起著重要作用。盡管Dio2也存在于正中隆起和弓狀核的星形膠質(zhì)細(xì)胞(astrocytes)中[18]，但選擇性敲除小鼠星形膠質(zhì)細(xì)胞中的Dio2對TRH的反饋無明顯影響[20]，說明星形膠質(zhì)細(xì)胞在HPT調(diào)控中作用較弱。在中樞神經(jīng)系統(tǒng)內(nèi)，Dio3表達(dá)分布廣泛，其表達(dá)能被T3所促進(jìn)，而伸長細(xì)胞也可表達(dá)Dio3[21]，但是否在影響促垂體的TRH神經(jīng)元的T3水平中起著重要作用尚不清楚。

若循環(huán)中的T4水平和T3水平下降，Dio2的主要作用是保持腦區(qū)局部T3濃度穩(wěn)定[22]。如在大腦皮質(zhì)，甲狀腺功能減退時會上調(diào)Dio2活性從而產(chǎn)生更多的T3，而甲狀腺功能亢進(jìn)時會下調(diào)Dio2活性[23]。因此，即使循環(huán)中的T4濃度在一個較寬的范圍內(nèi)變化，大腦皮層的局部T3濃度仍可保持不變[22]。伸長細(xì)胞中Dio2轉(zhuǎn)錄水平也受細(xì)胞內(nèi)甲狀腺激素的調(diào)控[24]，但是研究發(fā)現(xiàn)伸長細(xì)胞中Dio2基因表達(dá)的增加并不伴隨著Dio2活性的增加[25]。雖然甲狀腺功能減退導(dǎo)致大腦皮質(zhì)Dio2活性以超過4倍的速度增加[26]，但對下丘腦內(nèi)側(cè)基底部(MBH)的Dio2活性沒有影響[25]。另外，在碘缺乏的條件下，大腦大部分區(qū)域的Dio2活性增加而MBH的Dio2活性無改變[27]。由此可見，在MBH中甲狀腺激素對Dio2轉(zhuǎn)錄后活性減弱，表明Dio2在這一區(qū)域的主要作用并不是為了是維持局部T3水平的穩(wěn)定，而是有助于下丘腦接收外周甲狀腺激素水平變化的信號。這一作用極為重要，因為穩(wěn)定的下丘腦T3濃度反而會降低PVN的TRH神經(jīng)元反饋調(diào)節(jié)的敏感性。

此外，垂體促甲狀腺區(qū)也可表達(dá)Dio2，其可直接調(diào)控TSH的合成[28]。目前已經(jīng)證明可通過抑制Dio2來提高TSH水平，而無需依賴TRH水平表達(dá)的改變[29,30]。

2.3 甲狀腺激素轉(zhuǎn)運(yùn)體

甲狀腺激素必須通過甲狀腺激素轉(zhuǎn)運(yùn)體進(jìn)入細(xì)胞內(nèi)才能發(fā)揮作用，位于細(xì)胞內(nèi)的脫碘酶必須先將TH攝取入細(xì)胞才能發(fā)揮脫碘效應(yīng)。由于甲狀腺激素的高脂溶性，以前一直認(rèn)為其可以直接擴(kuò)散到細(xì)胞內(nèi)，但近30年甲狀腺激素的分子生物學(xué)研究顯示：甲狀腺激素主要通過甲狀腺激素轉(zhuǎn)運(yùn)體進(jìn)出細(xì)胞。甲狀腺激素的攝取是消耗ATP的主動轉(zhuǎn)運(yùn)過程。也就是說，細(xì)胞內(nèi)的T3、T4水平不僅依賴于脫碘酶，還與位于細(xì)胞膜上的甲狀腺素轉(zhuǎn)運(yùn)體有關(guān)。

目前，已知參與腦組織甲狀腺激素運(yùn)輸?shù)膬蓚€主要轉(zhuǎn)運(yùn)蛋白是非鈉依賴性有機(jī)陰離子轉(zhuǎn)運(yùn)多肽1C1(OATP1C1)和單羧酸轉(zhuǎn)運(yùn)蛋白8(MCT8)，分別屬于有機(jī)陰離子轉(zhuǎn)運(yùn)多肽(OATP)和單羧酸轉(zhuǎn)運(yùn)(MCT)家族[31]。OATP1C1對T3和T4均具有較強(qiáng)親和力，高度表達(dá)于血腦屏障、脈絡(luò)叢和伸長細(xì)胞[32, 33]。OATP1C1敲除動物模型近年才被構(gòu)建。研究顯示OATP1C1敲除小鼠的HPT軸不受影響[34]。這表明OATP1C1在對TRH神經(jīng)元的反饋調(diào)節(jié)中作用不大。相反，轉(zhuǎn)運(yùn)體MCT8主要表達(dá)于神經(jīng)元(包括促垂體區(qū)TRH神經(jīng)元)[35]和伸長細(xì)胞，其對T3親和力強(qiáng)[35]。研究發(fā)現(xiàn)MCT8敲除小鼠或破壞小鼠MCT8表達(dá)會導(dǎo)致腦中T3的含量減少而TRH的表達(dá)增加[36～38]，可見MCT8在TRH神經(jīng)元對T3的攝取起著重要作用。

2.4 甲狀腺激素受體

T3進(jìn)入TRH神經(jīng)元后，它通過與甲狀腺激素受體(TRs)結(jié)合發(fā)揮生物學(xué)效應(yīng)。TRs是配體依賴性受體，局部T3水平可影響TRs復(fù)合物與TREs的結(jié)合和解離，其通過識別并結(jié)合靶基因啟動子的TREs來調(diào)節(jié)基因轉(zhuǎn)錄。但TRs在調(diào)節(jié)負(fù)向靶基因作用中是依賴于其DNA的結(jié)合能力還是其與轉(zhuǎn)錄因子的相互作用尚不明確，TRs發(fā)揮負(fù)向調(diào)節(jié)的精確機(jī)制仍不清楚。甲狀腺激素受體(TRs)由兩個基因(TRα和TRβ)編碼，但不同的剪接和轉(zhuǎn)錄起始位點可產(chǎn)生不同的亞型。其中TRα1和TRβ1分布廣泛，而TRβ2的表達(dá)僅限于在特定類型的細(xì)胞如PVN的TRH神經(jīng)元[39]和垂體的促甲狀腺區(qū)[40,41]，被認(rèn)為是參與HPT軸負(fù)反饋調(diào)節(jié)的主要受體。而有研究表明伴有TRβ位點基因突變的患者會表現(xiàn)出中樞TH抵抗，即中樞神經(jīng)系統(tǒng)對TH的敏感性降低[42]，進(jìn)一步論證了這一點。另外，TRβ2表達(dá)受損的小鼠經(jīng)PTU干預(yù)后，TH水平下降而TRH和TSH水平上升，均體現(xiàn)了TRβ2在HPT軸負(fù)反饋調(diào)節(jié)中的重要作用[43,44]。

2.5 輔因子

TH結(jié)合TRs負(fù)向調(diào)節(jié)TRH和TSH亞基基因還需要輔因子的參與。輔因子(cofactor)(包括轉(zhuǎn)錄共激活因子和轉(zhuǎn)錄共抑制因子)是指與酶(酵素)結(jié)合且在催化反應(yīng)中必要的非蛋白質(zhì)化合物。輔因子并不直接與DNA結(jié)合，但可通過多種機(jī)制促進(jìn)或抑制靶基因的轉(zhuǎn)錄。T3存在時，其與TR結(jié)合形成復(fù)合物能促進(jìn)招募共激活因子，正向調(diào)節(jié)基因的啟動子，使相應(yīng)基因的轉(zhuǎn)錄增加；而T3缺失時會有助于TR招募核受體共抑制因子，導(dǎo)致相應(yīng)基因的轉(zhuǎn)錄減少。但TRs負(fù)向調(diào)控基因(如TRH和TSH亞基基因)表達(dá)的機(jī)制仍不清楚。體內(nèi)試驗顯示，共激活因子SRC-1為T3誘導(dǎo)抑制TSH所必需的，而缺乏該共激活因子的小鼠血中的T4和TSH水平增加[45,46]；同樣，小鼠表達(dá)的TRβ若不能正常招募SRC-1，則也有相同的表現(xiàn)[47]。若破壞TR與核受體共抑制劑NCoR1之間的相互作用，則有相反的效應(yīng)，這表明NCoR1對HPT的激活是必需的[48,49]。上述研究結(jié)果表明共激活因子和共抑制因子對負(fù)反饋機(jī)制至關(guān)重要，共激活因子和共抑制劑與TR的結(jié)合可能影響HPT軸的調(diào)定點。

2.6 焦谷氨酰肽酶Ⅱ

除了通過影響正中隆起的T3的可用性來調(diào)節(jié)TRH神經(jīng)元的反饋，最近發(fā)現(xiàn)伸長細(xì)胞能表達(dá)焦谷氨酰肽酶Ⅱ(PPⅡ)，PPⅡ能降解在正中隆起釋放的TRH，從而影響到達(dá)正中隆起的門靜脈的TRH水平[50,51]。PPⅡ是一種膜整合蛋白，由一個較小的N端胞內(nèi)區(qū)和一個含有酶活性區(qū)域的細(xì)胞外結(jié)構(gòu)域組成，其表達(dá)和活性受循環(huán)中TH的高度調(diào)控。有研究證明甲狀腺功能亢進(jìn)時，伸長細(xì)胞PPⅡ的表達(dá)量增加，從而減少到達(dá)垂體門靜脈的TRH水平，參與HPT的反饋調(diào)節(jié)[50,52]。此外，T3也可負(fù)向調(diào)節(jié)TRH所結(jié)合的特定細(xì)胞膜受體TRHR1的表達(dá)，降低其對TRH的敏感性[53～55]。由此可見，T3不僅可以調(diào)控TRH mRNA的表達(dá)，還可以影響TRH的產(chǎn)生、降解及其受體表達(dá)。

3 展望

目前，對HPT軸負(fù)反饋調(diào)節(jié)的分子機(jī)制已有了更加深入、全面的了解，但仍有許多問題有待解決。循環(huán)中甲狀腺激素水平的穩(wěn)定是由其對PVN的TRH神經(jīng)元的經(jīng)典負(fù)反饋機(jī)制所調(diào)控，而這種調(diào)控機(jī)制非常復(fù)雜，目前認(rèn)為此調(diào)控涉及的元件主要包括：脫碘酶、甲狀腺激素受體、甲狀腺激素轉(zhuǎn)運(yùn)體、輔因子、PPⅡ等。但這些引起定點改變的信號分子的通路仍有待進(jìn)一步闡明，在生理條件下哪些因素會產(chǎn)生影響并如何精密調(diào)控HPT軸仍有待探究。HPT軸整合機(jī)體內(nèi)環(huán)境和外部信號，其調(diào)節(jié)機(jī)制是多水平而復(fù)雜的，進(jìn)一步的研究HPT調(diào)控機(jī)制有助于闡明疾病引起HPT軸異常的機(jī)理，并為疾病提供可行的治療方法。

[1] Hollenberg A N, Monden T, Flynn T R,etal.. The human thyrotropin-releasing hormone gene is regulated by thyroid hormone through two distinct classes of negative thyroid hormone response elements[J]. Mol. Endocrinol., 1995, 9(5):540-550.

[2] Costa-e-Sousa R H, Hollenberg A N. Minireview: The neural regulation of the hypothalamic-pituitary-thyroid axis[J]. Endocrinology, 2012, 153(9):4128-4135.

[3] Nillni E A. Regulation of the hypothalamic thyrotropin releasing hormone (TRH) neuron by neuronal and peripheral inputs[J]. Front. Neuroendocrin., 2010, 31(2):134-156.

[4] Hollenberg A N. The role of the thyrotropin-releasing hormone (TRH) neuron as a metabolic sensor[J]. Thyroid, 2008, 18(2):131-139.

[5] Lechan R M, Fekete C. The TRH neuron: A hypothalamic integrator of energy metabolism[J]. Prog. Brain Res., 2006, 153:209-235.

[6] Martin J B, Boshans R, Reichlin S. Feedback regulation of TSH secretion in rats with hypothalamic lesions[J]. Endocrinology, 1970, 87(5):1032-1040.

[7] Beck-Peccoz P, Amr S, Menezes-Ferreira M M,etal.. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism: Effect of treatment with thyrotropin-releasing hormone[J]. New Engl. J. Med., 1985, 312(17):1085-1090.

[8] Nikrodhanond A A, Ortiga-Carvalho T M, Shibusawa N,etal.. Dominant role of thyrotropin-releasing hormone in the hypothalamic-pituitary-thyroid axis[J]. J. Biol. Chem., 2006, 281(8):5000-5007.

[9] Taylor T, Gesundheit N, Weintraub B D. Effects ofinvivobolus versus continuous TRH administration on TSH secretion, biosynthesis, and glycosylation in normal and hypothyroid rats[J]. Mol. Cell. Endocrinol., 1986, 46(3):253-261.

[10] Sugrue M L, Vella K R, Morales C,etal.. The thyrotropin-releasing hormone gene is regulated by thyroid hormone at the level of transcriptioninvivo[J]. Endocrinology, 2010, 151(2):793-801.

[11] Segerson T P, Kauer J, Wolfe H C,etal.. Thyroid hormone regulates TRH biosynthesis in the paraventricular nucleus of the rat hypothalamus[J]. Science, 1987, 238(4823):78-80.

[12] Perello M, Friedman T, Paez-Espinosa V,etal.. Thyroid hormones selectively regulate the posttranslational processing of prothyrotropin-releasing hormone in the paraventricular nucleus of the hypothalamus[J]. Endocrinology, 2006, 147(6):2705-2716.

[13] Fekete C, Lechan R M. Negative feedback regulation of hypophysiotropic thyrotropin-releasing hormone (TRH) synthesizing neurons: Role of neuronal afferents and type 2 deiodinase[J]. Front. Neuroendocrin., 2007, 28(2-3):97-114.

[14] Yamada M, Saga Y, Shibusawa N,etal.. Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene[J]. Proc. Natl. Acad. Sci. USA, 1997, 94(20):10862-10867.

[15] Galton V A, Schneider M J, Clark A S,etal.. Life without thyroxine to 3,5,3′-triiodothyronine conversion: Studies in mice devoid of the 5′-deiodinases[J]. Endocrinology, 2009, 150(6):2957-2963.

[16] Kakucska I, Rand W, Lechan R M. Thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus is dependent upon feedback regulation by both triiodothyronine and thyroxine[J]. Endocrinology, 1992, 130(5):2845-2850.

[17] Bianco A C. Minireview: Cracking the metabolic code for thyroid hormone signaling[J]. Endocrinology, 2011, 152(9):3306-3311.

[18] Diano S, Leonard J L, Meli R,etal.. Hypothalamic type II iodothyronine deiodinase: A light and electron microscopic study[J]. Brain Res., 2003, 976(1):130-134.

[19] Fekete C, Mihály E, Herscovici S,etal.. DARPP-32 and CREB are present in type 2 iodothyronine deiodinase-producing tanycytes: Implications for the regulation of type 2 deiodinase activity[J]. Brain Res., 2000, 862(1-2):154-161.

[20] Fonseca T L, Correa-Medina M, Campos M P O,etal.. Coordination of hypothalamic and pituitary T3 production regulates TSH expression[J]. J. Clin. Invest., 2013, 123(4):1492-1500.

[21] Ross A W, Helfer G, Russell L,etal.. Thyroid hormone signalling genes are regulated by photoperiod in the hypothalamus of F344 rats[J]. PLoS ONE, 2011, 6(6):e21351.

[22] Broedel O, Eravci M, Fuxius S,etal.. Effects of hyper- and hypothyroidism on thyroid hormone concentrations in regions of the rat brain[J]. Am. J. Physiol-Endoc. M., 2003, 285(3):E470-E480.

[23] Bianco A C, Salvatore D, Gereben B,etal.. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases[J]. Endocr. Rev., 2013, 23(1):38-89.

[24] Anguiano B, Quintanar A, Luna M,etal.. Neuroendocrine regulation of adrenal gland and hypothalamus 5′deiodinase activity. II. Effects of splanchnicotomy and hypophysectomy[J]. Endocrinology, 1995, 136(8):3346-3352.

[25] Diano S, Naftolin F, Goglia F,etal.. Fasting-induced increase in type II iodothyronine deiodinase activity and messenger ribonucleic acid levels is not reversed by thyroxine in the rat hypothalamus[J]. Endocrinology, 1998, 139(6):2879-2884.

[26] Leonard J L, Kaplan M M, Visser T J,etal.. Cerebral cortex responds rapidly to thyroid hormones[J]. Science, 1981, 214(4520):571-573.

[27] Serrano-Lozano A, Montiel M, Morell M,etal.. 5′deiodinase activity in brain regions of adult rats: Modifications in different situations of experimental hypothyroidism[J]. Brain Res. Bull., 1993, 30(5-6):611-616.

[28] Christoffolete M A, Ribeiro R, Singru P,etal.. Atypical expression of type 2 iodothyronine deiodinase in thyrotrophs explains the thyroxine-mediated pituitary thyrotropin feedback mechanism[J]. Endocrinology, 2006, 147(4):1735-1743.

[29] Burger A, Dinichert D, Nicod P,etal.. Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin, and thyrotropin: A drug influencing peripheral metabolism of thyroid hormones[J]. J. Clin. Invest., 1976, 58(2):255-259.

[30] Rosene M L, Wittmann G, Arrojo e Drigo R,etal.. Inhibition of the type 2 iodothyronine deiodinase underlies the elevated plasma TSH associated with amiodarone treatment[J]. Endocrinology, 2010, 151(12):5961-5970.

[31] Jansen J, Friesema E C H, Milici C,etal.. Thyroid hormone transporters in health and disease[J]. Thyroid, 2005, 15(8):757-768.

[32] Sugiyama D, Kusuhara H, Taniguchi H,etal.. Functional characterization of rat brain-specific organic anion transporter (Oatp14) at the blood-brain barrier: High affinity transporter for thyroxine[J]. J. Biol. Chem., 2003, 278(44):43489-43495.

[33] Kalló I, Mohácsik P, Vida B,etal.. A novel pathway regulates thyroid hormone availability in rat and human hypothalamic neurosecretory neurons[J]. PLoS ONE, 2012, 7(6):e37860.

[34] Mayerl S, Visser T J, Darras V M,etal.. Impact of Oatp1c1 deficiency on thyroid hormone metabolism and action in the mouse brain[J]. Endocrinology, 2012, 153(3):1528-1537.

[35] Heuer H, Maier M K, Iden S,etal.. The monocarboxylate transporter 8 linked to human psychomotor retardation is highly expressed in thyroid hormone-sensitive neuron populations[J]. Endocrinology, 2005, 146(4):1701-1706.

[36] Trajkovic M, Visser T J, Mittag J,etal.. Abnormal thyroid hormone metabolism in mice lacking the monocarboxylate transporter 8[J]. J. Clin. Invest., 2007, 117(3):627-635.

[37] Heuer H, Visser T. Minireview: Pathophysiological importance of thyroid hormone transporters[J]. Endocrinology, 2009, 150(3):1078-1083.

[38] Dumitrescu A M, Liao X H, Weiss R E,etal.. Tissue-specific thyroid hormone deprivation and excess in monocarboxylate transporter (Mct) 8-deficient mice[J]. Endocrinology, 2006, 147(9):4036-4043.

[39] Lechan R M, Qi Y, Jackson I M,etal.. Identification of thyroid hormone receptor isoforms in thyrotropin-releasing hormone neurons of the hypothalamic paraventricular nucleus[J]. Endocrinology, 1994, 135(1):92-100.

[40] Hodin R A, Lazar M A, Wintman B I,etal.. Identification of a thyroid hormone receptor that is pituitary-specific[J]. Science, 1989, 244(4900):76-79.

[41] Wood W M, Ocran K W, Gordon D F,etal.. Isolation and characterization of mouse complementary DNAs encoding α and β thyroid hormone receptors from thyrotrope cells: The mouse pituitary-specific β2 isoform differs at the amino terminus from the corresponding species from rat pituitary[J]. Mol. Endocrinol., 1991, 5(8):1049-1061.

[42] Safer J D, O’Connor M G, Colan S D,etal.. The thyroid hormone receptor-β gene mutation R383H is associated with isolated central resistance to thyroid hormone[J]. J. Clin. Endocr. Metab., 1999, 84(9):3099-3109.

[43] Abel E D, Ahima R S, Boers M E,etal.. Critical role for thyroid hormone receptor β2 in the regulation of paraventricular thyrotropin-releasing hormone neurons[J]. J. Clin. Invest., 2001, 107(8):1017-1023.

[44] Gauthier K, Chassande O, Plateroti M,etal.. Different functions for the thyroid hormone receptors TRα and TRβ in the control of thyroid hormone production and post-natal development[J]. EMBO J., 1999, 18(3):623-631.

[45] Weiss R E, Xu J, Ning G,etal.. Mice deficient in the steroid receptor co-activator 1 (SRC-1) are resistant to thyroid hormone[J]. EMBO J., 1999, 18(7):1900-1904.

[46] Takeuchi Y, Murata Y, Sadow P,etal.. Steroid receptor coactivator-1 deficiency causes variable alterations in the modulation of T3-regulated transcription of genesinvivo[J]. Endocrinology, 2002, 143(4):1346-1352.

[47] Ortiga-Carvalho T M, Shibusawa N, Nikrodhanond A,etal.. Negative regulation by thyroid hormone receptor requires an intact coactivator-binding surface[J]. J. Clin. Invest., 2005, 115(9):2517-2523.

[48] Fozzatti L, Lu C, Kim D W,etal.. Resistance to thyroid hormone is modulatedinvivoby the nuclear receptor corepressor (NCOR1)[J]. Proc. Natl. Acad. Sci. USA, 2011, 108(42):17462-17467.

[49] Astapova I, Vella K R, Ramadoss P,etal.. The nuclear receptor corepressor (NCoR) controls thyroid hormone sensitivity and the set point of the hypothalamic-pituitary-thyroid axis[J]. Mol. Endocrinol., 2011, 25(2):212-224.

[50] Sánchez E, Vargas M A, Singru P S,etal.. Tanycyte pyroglutamyl peptidase II contributes to regulation of the hypothalamic-pituitary-thyroid axis through glial-axonal associations in the median eminence[J]. Endocrinology, 2009, 150(5):2283-2291.

[51] Charli J L, Vargas M A, Cisneros M,etal.. TRH inactivation in the extracellular compartment: Role of pyroglutamyl peptidase II[J]. Neurobiology, 1998, 6(1):45-57.

[52] Marsili A, Sanchez E, Singru P,etal.. Thyroxine-induced expression of pyroglutamyl peptidase II and inhibition of TSH release precedes suppression of TRH mRNA and requires type 2 deiodinase[J]. J. Endocrinol., 2011, 211(1):73-78.

[53] Gershengorn M C. Bihormonal regulation of the thyrotropin-releasing hormone receptor in mouse pituitary thyrotropic tumor cells in culture[J]. J. Clin. Invest., 1978, 62(5):937-943.

[54] Yamada M, Monden T, Satoh T,etal.. Differential regulation of thyrotropin-releasing hormone receptor mRNA levels by thyroid hormoneinvivoandinvitro(GH3 cells)[J]. Biochem. Bioph. Res. Co., 1992, 184(1):367-372.

[55] Hinkle P M, Goh K B C. Regulation of thyrotropin-releasing hormone receptors and responses by L-triiodothyronine in dispersed rat pituitary cell cultures[J]. Endocrinology, 1982, 110(5):1725-1731.

ReviewonMolecularComponentsParticipatingNegativeFeedbackRegulationintheHypothalamus-pituitary-thyroidAxis

ZUO Weixing1, ZHANG Zhifei2, LIU Zhimin3*, WANG Chaoqun4*

1.The546thHospitalofChinesePeople’sLiberationArmy,Urumqi841700,China; 2.ClinicalMedicalCollege,WeifangMedicalUniversity,ShandongWeifang261053,China; 3.ChangzhengHospital,SecondMilitaryMedicalUniversity,Shanghai200003,China; 4.ChanghaiHospital,SecondMilitaryMedicalUniversity,Shanghai200433,China

Negative feedback regulation in the hypothalamic-pituitary-thyroid (HPT) axis primarily functions to maintain normal and circulating levels of thyroid hormone (TH). Hypophysiotropic thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus are believed to represent the regulatory core of the HPT axis. Studies have showed that not only circulating triiodothyronine (T3), tetraiodothyronine (T4) could also regulate intracellular T3 availability by type 2 deiodinase (Dio2) in tanycytes and responsible for negative feedback regulation of hypophysiotropic TRH. TH was transported into the hypophysiotropic TRH neurons by TH transporters and bound to thyroid hormone receptors (TRs), especially TRβ2, with the recruitment of coregulators by the TRs, participating in regulation of the corresponding target gene. In addition, tanycytes have been shown to express pyroglutamyl peptidase II (PPII), which degraded TRH releasing from TRH neurons and furthermore affected the TRH concentration in portal blood in different thyroid states. This article summarized molecular components of HPT axis regulation, which was aimed to provide reference for the scientific researches and clinical treatment of thyroid dysfunction or HPT axis abnormalities.

HPT axis; negative feedback; thyroid hormone; deiodinase

2017-05-22;接受日期2017-07-20

左衛(wèi)星，主治醫(yī)師，主要從事甲狀腺疾病臨床及基礎(chǔ)研究。E-mail：303.2006@163.com。*通信作者：劉志民，主任醫(yī)師，主要從事甲狀腺疾病臨床及基礎(chǔ)研究。E-mail：981857201@qq.com；王超群，住院醫(yī)師，主要從事甲狀腺疾病臨床及基礎(chǔ)研究。E-mail：wangcqvip@163.com

10.19586/j.2095-2341.2017.0048