秦源　郭永紅　王亞寧　賈戰(zhàn)生　張穎

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鐵調(diào)素調(diào)控與肝臟疾病引起的鐵代謝紊亂

秦源郭永紅王亞寧賈戰(zhàn)生張穎

710038西安第四軍醫(yī)大學(xué)唐都醫(yī)院全軍感染病診療中心(秦源，王亞寧，賈戰(zhàn)生，張穎)；西安交通大學(xué)醫(yī)學(xué)院第二附屬醫(yī)院感染科(郭永紅)通信作者：賈戰(zhàn)生，Email：jiazsh@fmmu.edu.cn；張穎，Email：zyfmmu@hotmail.com

機(jī)體鐵代謝涉及鐵離子的吸收、轉(zhuǎn)運(yùn)、利用、循環(huán)和儲存等過程。多種肝臟疾病可引起機(jī)體鐵代謝紊亂，包括病毒性肝炎和酒精性肝病等。鐵離子可通過芬頓(Fenton)反應(yīng)促進(jìn)細(xì)胞活性氧簇水平升高造成細(xì)胞損傷，因此組織中的鐵含量需維持在正常生理水平[1, 2]。2000年和2001年，Krause[3]和Park[4]等分別從人血清和尿中分離得到鐵調(diào)素。該分子是一種肝臟分泌的抗菌短肽，由25個氨基酸組成[5, 6]。鐵調(diào)素作為負(fù)性調(diào)控分子在維持鐵代謝穩(wěn)態(tài)中起著關(guān)鍵性作用, 并與多種鐵代謝疾病發(fā)病機(jī)制有關(guān)[7]。本文就相關(guān)肝臟疾病對鐵調(diào)素調(diào)控的影響及其與鐵代謝紊亂的關(guān)系作出如下綜述。

一、機(jī)體鐵代謝穩(wěn)態(tài)

人體缺乏有效的鐵離子排出途徑，小腸吸收的鐵離子和巨噬細(xì)胞釋放的鐵離子共同決定了血清鐵離子水平。食物中的Fe3+在胃和十二指腸酸性環(huán)境下溶解，由十二指腸細(xì)胞色素還原為可溶性Fe2+并與腸黏膜細(xì)胞頂端的二價(jià)鐵離子轉(zhuǎn)運(yùn)體1(Divalent Metal Transporter1，DMT1)結(jié)合進(jìn)入小腸上皮細(xì)胞。小腸上皮細(xì)胞中的一部分鐵離子與細(xì)胞內(nèi)去鐵蛋白結(jié)合生成鐵蛋白，另一部分通過與基底膜側(cè)膜鐵轉(zhuǎn)運(yùn)蛋白(Ferroportin，F(xiàn)PN)結(jié)合進(jìn)行跨細(xì)胞質(zhì)運(yùn)輸，鐵離子穿過細(xì)胞基底膜進(jìn)入血漿[8]。血漿中的鐵離子與轉(zhuǎn)鐵蛋白(Transferrin，Tf)結(jié)合后綁定于細(xì)胞膜表面轉(zhuǎn)鐵蛋白受體(Transferrin Receptor，TfR)形成Tf-TfR復(fù)合物，通過受體介導(dǎo)的內(nèi)吞作用進(jìn)入細(xì)胞。胞漿中的Tf-TfR復(fù)合物進(jìn)入內(nèi)涵體，其內(nèi)環(huán)境pH約為5.5，酸化的環(huán)境使Tf和TfR發(fā)生構(gòu)象改變釋放鐵離子，Tf和TfR則循環(huán)至細(xì)胞膜表面[9]。

當(dāng)機(jī)體鐵離子水平高于閾值時(shí)，肝臟分泌鐵調(diào)素循環(huán)至小腸。鐵調(diào)素通過作用于B2微球蛋白/組織相融性復(fù)合物/轉(zhuǎn)鐵蛋白受體1復(fù)合物(B2-Microglobulin/ Hemochromatosis Gene/Transferrin Receptor，B2M/HFE/TfR1)降低鐵調(diào)蛋白(Iron Regulatory Proteins，IRP)活性抑制鐵運(yùn)輸?shù)鞍妆磉_(dá)，減少小腸上皮細(xì)胞對鐵離子吸收。同時(shí)鐵調(diào)素也可使小腸上皮細(xì)胞膜表面FPN內(nèi)化降解，從而減少小腸上皮細(xì)胞鐵離子的輸出。對于巨噬細(xì)胞，研究發(fā)現(xiàn)上調(diào)鐵調(diào)素表達(dá)會直接抑制巨噬細(xì)胞輸出鐵離子導(dǎo)致胞內(nèi)鐵離子積累[10]。Nemeth[11]和Lim[12]等人研究表明阻斷鐵調(diào)素受體FPN表達(dá)可抑制巨噬細(xì)胞中鐵離子釋放到血漿。因此鐵調(diào)素偶聯(lián)鐵轉(zhuǎn)運(yùn)蛋白在維持機(jī)體鐵穩(wěn)態(tài)中發(fā)揮重要作用。

二、鐵調(diào)素調(diào)控機(jī)制

研究表明鐵調(diào)素表達(dá)受到多種外源性和內(nèi)源性因素調(diào)控，包括炎癥因子、低氧及其他機(jī)體信號通路[13]。骨形態(tài)發(fā)生蛋白/SMAD (Bone Morphogenetic Protein/Small Mother Against Decapentaplegic Homolog，BMP/SMAD)通路是調(diào)控鐵調(diào)素表達(dá)的重要途徑。BMP分子與鐵調(diào)素調(diào)節(jié)蛋白 (Hemojuvelin，HJV)共同結(jié)合于細(xì)胞表面BMP受體導(dǎo)致SMAD磷酸化并形成復(fù)合體。SMAD復(fù)合體轉(zhuǎn)入細(xì)胞核與鐵調(diào)素啟動子區(qū)BMP反應(yīng)元件結(jié)合調(diào)節(jié)鐵調(diào)素HAMP基因轉(zhuǎn)錄[14]。BMP分子如：BMP2、BMP4、BMP9和BMP6都參與了鐵調(diào)素表達(dá)調(diào)控。

細(xì)胞炎癥因子白介素-6(Interleukin-6，IL-6)在固有免疫中發(fā)揮作用。研究表明IL-6可通過激活信號轉(zhuǎn)化器及轉(zhuǎn)錄激活因子3 (Signal Transducer and Activator of Transcription 3，STAT3)通路完成對鐵調(diào)素調(diào)控。磷酸化的STAT3與HAMP基因啟動子區(qū)域STAT應(yīng)答元件結(jié)合增強(qiáng)HAMP基因轉(zhuǎn)錄活性，促進(jìn)鐵調(diào)素表達(dá)[15]。也有研究顯示在機(jī)體炎癥反應(yīng)中白介素-22(Interleukin-22，IL-22)和I型干擾素(Interferon，IFN)等細(xì)胞因子可通過STAT3信號通路激活鐵調(diào)素啟動子增加鐵調(diào)素表達(dá)[16]。

最近的研究表明，維生素D是肝細(xì)胞和單核細(xì)胞中潛在鐵調(diào)素調(diào)控因子。在維生素D缺乏的環(huán)境中肝臟促進(jìn)鐵調(diào)素合成，細(xì)胞內(nèi)和機(jī)體中的鐵調(diào)素水平升高并抑制細(xì)胞膜表達(dá)FPN。1，25-二羥維生素D通過綁定維生素D受體介導(dǎo)的鐵調(diào)素啟動子區(qū)抑制鐵調(diào)素mRNA翻譯[17]。鐵調(diào)素調(diào)控也受到胞內(nèi)信號影響，在內(nèi)源性介質(zhì)中CO發(fā)揮了重要作用。CO可阻斷STAT-3磷酸化和內(nèi)質(zhì)網(wǎng)應(yīng)激，抑制鐵調(diào)素表達(dá)[18]。此外有研究報(bào)道低氧環(huán)境可抑制鐵調(diào)素表達(dá)，低氧誘導(dǎo)因子能間接的通過促進(jìn)HJV分解抑制鐵調(diào)素表達(dá)增強(qiáng)小腸對鐵離子的吸收、攝取和血紅素合成，保證充足的鐵離子用于紅細(xì)胞生成[19]。

三、肝臟疾病引起的鐵代謝紊亂

肝臟是儲存鐵離子的主要器官，為新陳代謝提供鐵離子。慢性丙型肝炎、乙型肝炎及酒精性肝病均可引發(fā)機(jī)體鐵代紊亂。

慢性丙型肝炎患者常出現(xiàn)輕到中度的肝鐵過載癥狀，對肝臟造成損害。已有研究證實(shí)，慢性丙型肝炎患者的肝鐵離子平均含量接近0.50 g至0.69 g，是健康人肝鐵離子含量的2～5倍。一些臨床研究報(bào)道慢性丙型肝炎患者鐵過載主要集中在網(wǎng)狀內(nèi)皮組織系統(tǒng)，而Fiel等[20]研究表明慢性丙型肝炎患者鐵過載主要存在于肝細(xì)胞中。Fujita等[7]認(rèn)為慢性丙型肝炎患者肝臟鐵調(diào)素mRNA水平與血清鐵蛋白濃度及肝臟鐵沉積的程度均有關(guān)聯(lián)性。Miura等[21]發(fā)現(xiàn)，丙型肝炎病毒(Hepatitis C Virus，HCV)誘導(dǎo)的活性氧簇(Reactive Oxygen Species，ROS)通過增加組蛋白乙?；D(zhuǎn)移酶活性(Histone Deacetylase，HDAC)抑制了CCAAT/增強(qiáng)子綁定蛋白α(CCAAT/Enhancer-Binding Protein α，C/EBPα)與鐵調(diào)素啟動子綁定活性。鐵調(diào)素表達(dá)隨著ROS水平增加而下調(diào)[22, 23]。已有研究證實(shí)，肝細(xì)胞中STAT3磷酸化與IFN誘導(dǎo)的抗HCV效率有關(guān)[31]。慢性丙型肝炎患者血清IL-6水平升高增加了STAT3促進(jìn)鐵調(diào)素表達(dá)的可能性，但HCV誘導(dǎo)ROS引起的鐵調(diào)素轉(zhuǎn)錄抑制作用更為明顯[24]。

乙型肝炎患者血清鐵調(diào)素水平與鐵代謝密切相關(guān)。潘衛(wèi)華等[25]對不同類型的乙型肝炎患者血清鐵、鐵蛋白、鐵調(diào)素及炎性因子指標(biāo)相關(guān)性研究表明，乙型肝炎患者鐵蛋白含量與病情嚴(yán)重程度呈正相關(guān)。乙型肝炎引起的炎癥反應(yīng)會抑制鐵調(diào)素表達(dá)，重型乙型肝炎患者血清鐵水平顯著升高。Yonal[26]和Jaroszewicz[27]等研究表明，乙型肝炎患者鐵調(diào)素水平隨病情不同發(fā)展階段波動，肝硬化階段患者血清鐵調(diào)素前體顯著降低且與肝功能損害程度呈負(fù)相關(guān)。在肝癌患者癌組織中鐵調(diào)素表達(dá)顯著下調(diào)[7]。Olmez等[28]發(fā)現(xiàn)與健康志愿者和丙型肝炎患者相比，乙型肝炎患者血清中的鐵調(diào)素前體水平明顯下調(diào)，并與肝纖維化程度呈負(fù)相關(guān)。也有研究顯示，乙型肝炎、丙型肝炎患者體內(nèi)鐵調(diào)素水平都下調(diào)并導(dǎo)致FPN表達(dá)增多引起血清鐵水平升高及肝鐵過載, 但丙型肝炎患者肝鐵過載癥狀更顯著[29-31]。IL-6可激活STAT3通路促進(jìn)鐵調(diào)素表達(dá)，羅光成[32]和朱濤[33]等研究表明慢性乙型肝炎非活動組和活動組IL-6水平均高于對照組，患者血清IL-6水平隨著病情加重顯著升高，提示慢性乙型肝炎患者機(jī)體鐵調(diào)素表達(dá)受到抑制可能是包括STAT3和BMP/SMAD在內(nèi)的多種信號通路共同調(diào)控結(jié)果。這與慢性丙型肝炎患者血清IL-6水平升高但鐵調(diào)素表達(dá)仍受到抑制的現(xiàn)象一致。此外鐵離子對乙型肝炎病毒(Hepatitis B Virus，HBV)持續(xù)感染有重要作用，HBV更容易感染鐵含量高的肝細(xì)胞[34]，抗病毒治療可顯著促進(jìn)鐵調(diào)素表達(dá)從而減輕肝臟鐵過載癥狀。

酒精性肝病患者常伴有肝臟鐵過載癥狀[35]，鐵離子和酒精對肝臟損傷具有協(xié)同作用[36]。研究發(fā)現(xiàn)酒精代謝可促進(jìn)活性氧化簇生成，氧化應(yīng)激反應(yīng)抑制了鐵調(diào)素表達(dá)從而導(dǎo)致腸上皮細(xì)胞攝取鐵離子增加和肝臟鐵過載[37]。Harrison等[38]發(fā)現(xiàn)，酒精代謝介導(dǎo)氧化應(yīng)激反應(yīng)產(chǎn)生的活性氧化簇可通過C/EBPα抑制鐵調(diào)素轉(zhuǎn)錄，而酒精代謝酶抑制劑可阻斷酒精代謝介導(dǎo)的肝臟鐵調(diào)素變化，如乙酰半胱氨酸和維生素E等抗氧化劑。因此對于通過抑制C/EBPα活性干擾鐵調(diào)素轉(zhuǎn)錄而言，慢性丙型肝炎引起的肝鐵過載和酒精性肝病導(dǎo)致的肝鐵過載內(nèi)在機(jī)制有一定的相似性。

四、總結(jié)與展望

綜上所述，慢性丙型肝炎、乙型肝炎及酒精性肝病患者均存在不同程度的鐵代謝紊亂，而鐵調(diào)素調(diào)控與這些肝臟疾病密切相關(guān)，且慢性丙型肝炎與乙型肝炎之間、慢性丙型肝炎與酒精性肝病之間對鐵調(diào)素表達(dá)的抑制機(jī)制有一定關(guān)聯(lián)和相似性。總之，闡明鐵調(diào)素表達(dá)和相關(guān)信號通路之間的關(guān)系將促進(jìn)病毒性肝炎和酒精性肝病的控制和治療。

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(本文編輯：張苗)

基金項(xiàng)目：國家自然科學(xué)基金(81273218)

(收稿日期：2015-12-25)