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)學院臨床醫(yī)學院, 山東 濰坊 261053；3.第二軍醫(yī)大學附屬長征醫(yī)院, 上海 200003；4.第二軍醫(yī)大學附屬長海醫(yī)院, 上海 200433

參與下丘腦-垂體-甲狀腺軸負反饋調(diào)控的分子元件研究進展

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)學院臨床醫(yī)學院, 山東 濰坊 261053；3.第二軍醫(yī)大學附屬長征醫(yī)院, 上海 200003；4.第二軍醫(yī)大學附屬長海醫(yī)院, 上海 200433

下丘腦-垂體-甲狀腺(hypothalamic-pituitary-thyroid，HPT)軸負反饋調(diào)節(jié)是維持血清甲狀腺激素(thyroid hormone,TH)水平穩(wěn)定的最重要的機制。目前，普遍認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)伸長細胞的脫碘酶2(Dio2)催化脫碘來影響細胞中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運體攝取循環(huán)中的TH，而TH進入PVN的TRH神經(jīng)元或垂體促甲狀腺區(qū)細胞核與甲狀腺激素受體(TRs)(特別是TRβ2)結合后，可招募輔因子，共同參與相應靶基因的調(diào)控。此外，中樞神經(jīng)系統(tǒng)伸長細胞表達的焦谷氨酰肽酶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研究及臨床治療提供參考。

HPT軸；負反饋；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)機制，它對于機體維持穩(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。雖然HPT軸的反饋調(diào)節(jié)現(xiàn)象早已被發(fā)現(xiàn)，但其分子機制的研究仍在不斷推進。故本文將對參與HPT軸中樞負反饋調(diào)控的重要信號分子(包括促甲狀腺激素釋放激素、脫碘酶、甲狀腺激素轉運體、甲狀腺激素受體、輔因子、焦谷氨酰肽酶Ⅱ)進行綜述，以期為相關研究提供參考。

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個負向甲狀腺激素反應元件(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結合，進而介導甲狀腺激素對TRH靶基因的負反饋調(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，還需要多種分子的共同參與才能使循環(huán)中的TH進入中樞神經(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發(fā)揮生物學效應的激素，甲狀腺激素必須通過甲狀腺激素轉運體穿過血-腦和血-腦脊液屏障最終進入TRH神經(jīng)元細胞核內(nèi)才能發(fā)揮其調(diào)控作用。進入細胞后，其不同活性形式的三碘甲狀腺原氨酸(T3)、甲狀腺素(T4)相互轉化受細胞(如伸長細胞)內(nèi)脫碘酶(Dio)的調(diào)控。進入TRH神經(jīng)元細胞核后，與大多數(shù)核受體一樣，甲狀腺激素對基因的轉錄調(diào)控還依賴于甲狀腺激素受體及輔因子的參與。另外，伸長細胞表達的焦谷氨酰肽酶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、甲狀腺激素轉運體、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)元的缺失會嚴重損害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)激素原轉化酶加工而來的三肽，通過正中隆起分泌到達垂體，刺激TSH的合成和釋放。TRH的轉錄[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)機制[11]。當循環(huán)中甲狀腺激素水平升高時，TRH基因表達下降；而甲狀腺功能減退時，TRH基因表達增加[13]。研究表明甲狀腺激素對TRH轉錄的調(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)主導地位。但在甲狀腺功能嚴重減退、TRH較低時，垂體依然能夠促進TSH的合成[8,14]，說明TH除了在TRH神經(jīng)元水平上發(fā)生負反饋作用，還會在TSH的水平上進行調(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

早期研究認為在循環(huán)中只有T3水平可影響HPT軸的負反饋調(diào)節(jié)，但Kakucska等[15]發(fā)現(xiàn)甲減大鼠循環(huán)中的T3水平恢復正常而不干預T4時，下丘腦PVN的TRH mRNA并未恢復正常。只有循環(huán)中的T3水平嚴重高于正常值時，TRH mRNA的表達才降到正常范圍內(nèi)[16]。由此，研究者認為循環(huán)中T4在中樞神經(jīng)系統(tǒng)中轉化為T3是參與反饋調(diào)節(jié)機制的一個重要環(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轉化為活性更強的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)細胞及第三腦室細胞中表達，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胞內(nèi)T3的可用性[17]，腦組織中的T4在Dio2催化下轉換成活性更強的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通過脫碘酶轉換而來的。而下丘腦脫碘酶主要在伸長細胞(tanycytes)中表達[18, 19]。伸長細胞是位于第三腦室底部腹側壁和正中隆起處室管膜上的特殊膠質(zhì)細胞，是血和腦脊液之間的選擇性雙向轉運通路。目前認為伸長細胞中的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)細胞(astrocytes)中[18]，但選擇性敲除小鼠星形膠質(zhì)細胞中的Dio2對TRH的反饋無明顯影響[20]，說明星形膠質(zhì)細胞在HPT調(diào)控中作用較弱。在中樞神經(jīng)系統(tǒng)內(nèi)，Dio3表達分布廣泛，其表達能被T3所促進，而伸長細胞也可表達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]。伸長細胞中Dio2轉錄水平也受細胞內(nèi)甲狀腺激素的調(diào)控[24]，但是研究發(fā)現(xiàn)伸長細胞中Dio2基因表達的增加并不伴隨著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水平表達的改變[29,30]。

2.3 甲狀腺激素轉運體

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

目前，已知參與腦組織甲狀腺激素運輸?shù)膬蓚€主要轉運蛋白是非鈉依賴性有機陰離子轉運多肽1C1(OATP1C1)和單羧酸轉運蛋白8(MCT8)，分別屬于有機陰離子轉運多肽(OATP)和單羧酸轉運(MCT)家族[31]。OATP1C1對T3和T4均具有較強親和力，高度表達于血腦屏障、脈絡叢和伸長細胞[32, 33]。OATP1C1敲除動物模型近年才被構建。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，轉運體MCT8主要表達于神經(jīng)元(包括促垂體區(qū)TRH神經(jīng)元)[35]和伸長細胞，其對T3親和力強[35]。研究發(fā)現(xiàn)MCT8敲除小鼠或破壞小鼠MCT8表達會導致腦中T3的含量減少而TRH的表達增加[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進入TRH神經(jīng)元后，它通過與甲狀腺激素受體(TRs)結合發(fā)揮生物學效應。TRs是配體依賴性受體，局部T3水平可影響TRs復合物與TREs的結合和解離，其通過識別并結合靶基因啟動子的TREs來調(diào)節(jié)基因轉錄。但TRs在調(diào)節(jié)負向靶基因作用中是依賴于其DNA的結合能力還是其與轉錄因子的相互作用尚不明確，TRs發(fā)揮負向調(diào)節(jié)的精確機制仍不清楚。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的表達僅限于在特定類型的細胞如PVN的TRH神經(jīng)元[39]和垂體的促甲狀腺區(qū)[40,41]，被認為是參與HPT軸負反饋調(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]，進一步論證了這一點。另外，TRβ2表達受損的小鼠經(jīng)PTU干預后，TH水平下降而TRH和TSH水平上升，均體現(xiàn)了TRβ2在HPT軸負反饋調(diào)節(jié)中的重要作用[43,44]。

2.5 輔因子

TH結合TRs負向調(diào)節(jié)TRH和TSH亞基基因還需要輔因子的參與。輔因子(cofactor)(包括轉錄共激活因子和轉錄共抑制因子)是指與酶(酵素)結合且在催化反應中必要的非蛋白質(zhì)化合物。輔因子并不直接與DNA結合，但可通過多種機制促進或抑制靶基因的轉錄。T3存在時，其與TR結合形成復合物能促進招募共激活因子，正向調(diào)節(jié)基因的啟動子，使相應基因的轉錄增加；而T3缺失時會有助于TR招募核受體共抑制因子，導致相應基因的轉錄減少。但TRs負向調(diào)控基因(如TRH和TSH亞基基因)表達的機制仍不清楚。體內(nèi)試驗顯示，共激活因子SRC-1為T3誘導抑制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，這表明NCoR1對HPT的激活是必需的[48,49]。上述研究結果表明共激活因子和共抑制因子對負反饋機制至關重要，共激活因子和共抑制劑與TR的結合可能影響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)伸長細胞能表達焦谷氨酰肽酶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)域的細胞外結構域組成，其表達和活性受循環(huán)中TH的高度調(diào)控。有研究證明甲狀腺功能亢進時，伸長細胞PPⅡ的表達量增加，從而減少到達垂體門靜脈的TRH水平，參與HPT的反饋調(diào)節(jié)[50,52]。此外，T3也可負向調(diào)節(jié)TRH所結合的特定細胞膜受體TRHR1的表達，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，還可以影響TRH的產(chǎn)生、降解及其受體表達。

3 展望

目前，對HPT軸負反饋調(diào)節(jié)的分子機制已有了更加深入、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)典負反饋機制所調(diào)控，而這種調(diào)控機制非常復雜，目前認為此調(diào)控涉及的元件主要包括：脫碘酶、甲狀腺激素受體、甲狀腺激素轉運體、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軸整合機體內(nèi)環(huán)境和外部信號，其調(diào)節(jié)機制是多水平而復雜的，進一步的研究HPT調(diào)控機制有助于闡明疾病引起HPT軸異常的機理，并為疾病提供可行的治療方法。

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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研究。E-mail：wangcqvip@163.com

10.19586/j.2095-2341.2017.0048