宋士一, 劉春燕, 姜 雯, 王 進(jìn), 張 圓

(沈陽師范大學(xué) 生命科學(xué)學(xué)院, 沈陽 110034)

哺乳動(dòng)物冬眠調(diào)控機(jī)制中MicroRNA的作用

宋士一, 劉春燕, 姜 雯, 王 進(jìn), 張 圓

(沈陽師范大學(xué) 生命科學(xué)學(xué)院, 沈陽 110034)

冬眠是很多哺乳動(dòng)物在低溫、食物缺乏和缺氧等極端環(huán)境下選擇的應(yīng)對(duì)技巧,表現(xiàn)為體核溫度降低,心率、代謝率和呼吸率下降等。在不同冬眠動(dòng)物的不同組織中,這一過程伴隨著生理水平和生化水平的調(diào)節(jié)變化,此外,微小非編碼核酸族(microRNA, miRNA)也起到潛在的調(diào)控作用。了解miRNA的代謝過程及主要作用機(jī)制有助于理解其作用。miRNA在冬眠動(dòng)物體內(nèi)調(diào)控糖酵解與糖異生、氨基酸代謝、胰島素信號(hào)通路、脂肪酸代謝和脂代謝穩(wěn)態(tài)等代謝途徑中的靶物,從而潛在地調(diào)控冬眠時(shí)的能量來源從碳水化合物轉(zhuǎn)化為脂肪;miRNA能幫助保護(hù)心肌、骨骼肌、腎臟、肝臟和大腦等組織免受低溫帶來的傷害,保護(hù)機(jī)體度過惡劣環(huán)境并且在冬眠結(jié)束之后蘇醒。對(duì)不同的冬眠物種及其不同器官組織中miRNA的研究有利于加深對(duì)冬眠機(jī)制的理解。

哺乳動(dòng)物; 冬眠; MicroRNA; 靶物

0 引 言

為了在低溫或缺少食物的極端環(huán)境條件中存活下來,一些哺乳動(dòng)物在冬季會(huì)選擇冬眠。冬眠是指一些哺乳動(dòng)物在冬季出現(xiàn)的非活躍狀態(tài),此時(shí)動(dòng)物的體溫和代謝率降低。冬季過后動(dòng)物恢復(fù)活躍狀態(tài),體溫和代謝率又恢復(fù)到正常水平[1]。與非冬眠期相比,哺乳動(dòng)物在冬眠時(shí),體核溫度很低 (Tb≈4 ℃),代謝速度降低到原來的1/20左右[2],冬眠時(shí)還有其他顯著的生理變化,包括血流量減少、呼吸頻率降低和心率降低等[3]。這些變化與能量消耗相關(guān),也與相關(guān)的基因轉(zhuǎn)錄和翻譯調(diào)節(jié)有關(guān),即冬眠時(shí)動(dòng)物體內(nèi)存在蛋白質(zhì)轉(zhuǎn)錄水平及其表達(dá)水平的調(diào)控[4]。微小RNA (microRNA, miRNA) 是一種內(nèi)源性的單鏈非編碼小RNA,具有基因轉(zhuǎn)錄后水平調(diào)控作用[5-6],研究發(fā)現(xiàn),miRNA在冬眠過程中有潛在的調(diào)控作用,其在低溫、缺食或缺氧等條件下參與調(diào)控生理變化和生物化學(xué)變化[7]。本文綜述了miRNA在冬眠期調(diào)控與代謝抑制有關(guān)的糖脂代謝途徑和保護(hù)心肌等組織的研究進(jìn)展,為進(jìn)一步研究哺乳動(dòng)物冬眠期的分子水平機(jī)制變化提供理論基礎(chǔ)。

1 miRNA的合成及作用機(jī)制

miRNA是短鏈(約21個(gè)核苷酸)非編碼RNA轉(zhuǎn)錄體,其在轉(zhuǎn)錄后調(diào)控多細(xì)胞動(dòng)物、植物和原生動(dòng)物的基因表達(dá)。Lin-4是在秀麗線蟲中發(fā)現(xiàn)的第1個(gè)miRNA,它可以抑制包括LIN-14在內(nèi)的靶基因的表達(dá)[8]。之后在其他幾個(gè)物種中發(fā)現(xiàn)和描述了幾百種miRNA。由RNA聚合酶Ⅱ作用下產(chǎn)生的初期轉(zhuǎn)錄物稱為pri-miRNA,pri-miRNA擁有一個(gè)或者數(shù)個(gè)發(fā)夾結(jié)構(gòu),一個(gè)發(fā)卡結(jié)構(gòu)通常包括長30bp的不完整單鏈RNA片段[9]。pri-miRNA在細(xì)胞核中通過與Drosha(核糖核酸酶Ⅲ酶)和迪格奧爾格綜合征關(guān)鍵區(qū)基因8結(jié)合,這個(gè)結(jié)構(gòu)被識(shí)別和處理后形成前體miRNA(pre-miRNA)[10]。pre-miRNA是約70個(gè)核苷酸長度的發(fā)夾結(jié)構(gòu),從細(xì)胞核中通過輸出蛋白-5到細(xì)胞質(zhì)中[11]。

在細(xì)胞質(zhì)中,pre-miRNA被Dicer酶切開。Dicer酶將發(fā)卡的結(jié)合部分分開產(chǎn)生一個(gè)miRNA和miRNA*副本[12]。2條鏈中間的一個(gè)會(huì)與Argonaute(AGO)蛋白家族的成員和其他的蛋白結(jié)合,例如與GW182結(jié)合,之后形成miRNA-誘導(dǎo)沉默復(fù)合體;另一條則會(huì)降解掉[12]。miRNA與靶轉(zhuǎn)錄本的相互作用會(huì)抑制和/或啟動(dòng)mRNA衰變。據(jù)估計(jì),miRNA調(diào)控超過60%的蛋白質(zhì)編碼基因[13]。另外,miRNA還能通過靶向結(jié)合另一個(gè)miRNA的初級(jí)轉(zhuǎn)錄來調(diào)控其功能[14]。miRNA的功能與靶物基因的功能有關(guān),通過觀察靶物的功能就能理解miRNA的功能,例如脊椎動(dòng)物的miR-17～ 92族的靶基因參與生長控制[15]。

2 冬眠時(shí)生理水平和生化水平受到的適應(yīng)性調(diào)節(jié)

小型哺乳動(dòng)物會(huì)采取一種生理和行為上的適應(yīng)行為來應(yīng)對(duì)威脅生存的極端條件,即在冬季(或者晚秋和早春)會(huì)出現(xiàn)昏睡狀態(tài), 這一過程伴隨著體溫和代謝的降低。

關(guān)于哺乳動(dòng)物冬眠的研究越來越關(guān)注生物化學(xué)機(jī)制和分子機(jī)制。研究者已經(jīng)發(fā)現(xiàn)在冬眠時(shí)存在主要能量消耗過程的抑制現(xiàn)象,其中涉及到相關(guān)基因轉(zhuǎn)錄的抑制和蛋白翻譯的抑制[16]。北極黃鼠(Spermophilusparryii)的基因組學(xué)和蛋白質(zhì)組學(xué)表達(dá)數(shù)據(jù)的分析顯示基因和蛋白水平的變化不一致,這說明存在轉(zhuǎn)錄后機(jī)制的參與[17]。

糖酵解、糖異生、脂肪酸代謝和氨基酸代謝等代謝途徑中有些基因在長時(shí)間低溫生存情況下存在過表達(dá)的現(xiàn)象[18]。蝙蝠(Myotisricketti) 冬眠時(shí)白色脂肪組織(White Adipose Tissue, WAT)中胰島素受體底物顯著上調(diào)表明葡萄糖的吸收受到抑制,5′一磷酸腺苷激活的蛋白激酶的減少可以促進(jìn)糖異生,證明miRNA通過抑制葡萄糖代謝,使脂肪成為主要的能量來源[19]。蛋白可逆磷酸化會(huì)影響一些酶的活性從而降低代謝率,這一機(jī)制會(huì)明顯抑制一些參與碳水化合物分解代謝的酶的作用,進(jìn)而在冬眠過程中使消耗碳水化合物轉(zhuǎn)化為消耗脂質(zhì)[20]。

關(guān)于冬眠的其他翻譯后機(jī)制也有報(bào)道。哺乳動(dòng)物多紋黃鼠(Ictidomystridecemlineatus)冬眠時(shí)大腦組織中的蛋白磷酸化作用是顯著增加的,這對(duì)于大腦缺血耐受有重要作用[21]。多紋黃鼠冬眠組織中的泛素共軛濃度也增加2～3倍,這在冬眠時(shí)會(huì)對(duì)蛋白質(zhì)水解率有潛在的降低作用[22]。

3 miRNA在應(yīng)對(duì)低溫壓力和保護(hù)機(jī)體中的作用

為了更好地理解miRNA的變化及其和mRNA的相互作用以及后續(xù)的翻譯抑制,在細(xì)胞系和動(dòng)物模型等典型生物醫(yī)學(xué)系統(tǒng)中進(jìn)行了關(guān)于miRNA合成過程中關(guān)鍵物質(zhì)及其調(diào)控mRNA的研究。北極黃鼠的WAT和褐色脂肪(Brown Adipose Tissue,BAT)及蝙蝠的腦中在冬眠期調(diào)控miRNA生成過程中的Dicer酶的含量沒有明顯變化[23]。

用高通量Illumina平行測(cè)序技術(shù)、Agilent科技公司微陣列芯片和RT-PCR檢測(cè)的冬眠期北極黃鼠的肝臟中miR-320、miR-378、miR-451和miR-486的表達(dá)不同[24]。通過對(duì)它們的潛在作用進(jìn)行分析,可知它們?cè)诙咂谝种萍?xì)胞生長。多紋黃鼠冬眠期WAT中l(wèi)et-7a、let-7b、miR-107、miR-150、miR-222和miR-31表達(dá)降低,然而miR-143、miR-200a和miR-519d表達(dá)增加;冬眠期BAT中miR-103a、miR-107、miR-125b、miR-21、miR-221和miR-31表達(dá)降低,另一種唯一的在此期間高表達(dá)的miRNA為miR-138(高出對(duì)照組2.91±0.8倍);WAT和BAT中低表達(dá)的miRNA與絲裂原活化蛋白激酶的信號(hào)調(diào)控相聯(lián)系,而在WAT高表達(dá)的miRNA與轉(zhuǎn)化生長因子的信號(hào)作用有關(guān),表明WAT與BAT細(xì)胞在冬眠期活躍分解以供能,但生長減少[25]。

不同表達(dá)的miRNA在代謝降低的動(dòng)物模型中能夠調(diào)控脂代謝穩(wěn)態(tài)、胰島素信號(hào)通路和葡萄糖代謝通路中靶轉(zhuǎn)錄本的翻譯。例如,參與脂肪酸生物合成的幾個(gè)酶就是miRNA的靶物,包括這個(gè)通路中第1步反應(yīng)的酶:將乙酰-輔酶A轉(zhuǎn)換為丙二酰-輔酶A的乙酰-輔酶A羧化酶(acetyl-CoA carboxylase, ACC)。當(dāng)miR-144和miR-451在小鼠主動(dòng)脈血管平滑肌細(xì)胞中過表達(dá)時(shí),它可以抑制ACC蛋白表達(dá)[26]。在關(guān)于大鼠的研究中ACC是miR-34的直接靶物[27]。在骨肉瘤中,另一個(gè)參與脂肪酸合成的關(guān)鍵蛋白脂肪酸合成酶受miR-195的調(diào)控[28]。其他與脂質(zhì)穩(wěn)態(tài)有關(guān)的miRNA包括miR-143,它調(diào)控脂肪前體細(xì)胞中的增強(qiáng)子結(jié)合蛋白α和脂肪酸結(jié)合蛋白4的表達(dá)。另外,miR-33使肉毒堿棕櫚酰轉(zhuǎn)移酶表達(dá)沉默[29]。miR-130的靶物是可以影響脂肪存儲(chǔ)和人類脂肪組織能量平衡的轉(zhuǎn)錄因子過氧化物酶體增殖物激活受體γ[30]。

關(guān)于miRNA調(diào)節(jié)胰島素分泌和信號(hào)的例子也有報(bào)道,miR-375具有胰島特異性,它對(duì)胰島素分泌有影響[31]。在Ⅱ型糖尿病大鼠模型的研究中,高血糖癥出現(xiàn)時(shí)miR-335高表達(dá),能夠抑制參與胰島素釋放的靶mRNA突觸融合蛋白結(jié)合蛋白[32]。小鼠胰腺β細(xì)胞系中,miR-29a、miR-29b和miR-124的靶物單羧酸轉(zhuǎn)運(yùn)蛋白1可以將單糖轉(zhuǎn)變成丙酮酸,說明其對(duì)胰島素釋放有潛在的作用[33]。

在對(duì)葡萄糖穩(wěn)態(tài)的研究中,miR-103和miR-107增加肥胖老鼠的葡萄糖攝取[34]。在人肝癌細(xì)胞株中,miR-33可以影響葡萄糖代謝的一個(gè)重要中介去乙?；?的表達(dá)[35]?？傊?通過這些研究可以看到miRNA在各種生物模型中,對(duì)調(diào)節(jié)主要代謝通路的重要性,提示miRNA在與寒冷有關(guān)的代謝降低過程中對(duì)協(xié)調(diào)類似通路存在潛在影響。

在幫助不同物種動(dòng)物應(yīng)對(duì)來自低溫的壓力時(shí),miRNA起到保護(hù)心肌、骨骼肌、腎臟和肝臟的重要作用。多紋黃鼠冬眠期與產(chǎn)熱期的組織相比,心肌和骨骼肌中miR-24的表達(dá)降低,骨骼肌中miR-122a的表達(dá)降低,腎臟中miR-1和miR-21明顯增加[36]。miR-106b可以調(diào)控低氧誘導(dǎo)的轉(zhuǎn)錄因子-1α,它在冬眠的多紋黃鼠和蝙蝠的骨骼肌中表達(dá)顯著降低[37]。北極黃鼠肌肉中富集的miR-486過表達(dá),抑制磷酸酶張力蛋白同源物和Foxo1的表達(dá),從而減少對(duì)磷脂酰肌醇-3-激酶通路的抑制作用,表明其在冬眠條件下調(diào)節(jié)細(xì)胞周期的潛在作用[38]。冬眠期小型褐蝙蝠(Myotislucifugus)的骨骼肌中 miR-1a-1、miR-29b、miR-181b、miR-15a、miR-20a、miR-206和miR-128-1的水平增加,其相關(guān)的靶物肌肉生長抑制素水平降低,在冬眠蝙蝠體內(nèi)這些miRNA可以通過調(diào)控肌肉特異性蛋白,預(yù)防肌萎縮[39]。

冬眠陣中蝙蝠大腦內(nèi)miR-21、miR-29b、miR-103、miR-107、miR-124a、miR-132、miR-183和miR-501表達(dá)增加,生物信息學(xué)分析顯示這些miRNA主要參與2個(gè)過程:黏著斑作用和軸突導(dǎo)向,提示蝙蝠冬眠期大腦功能與miRNA對(duì)神經(jīng)細(xì)胞和適應(yīng)性神經(jīng)保護(hù)作用的調(diào)節(jié)是有關(guān)的[40]。與活躍期相比,冬眠期多紋黃鼠大腦組織中的miR-200和miR-182家族下調(diào),這些miRNA參與不同的泛素類蛋白修飾物及它們與其他蛋白的結(jié)合,活性降低,通過上述的ULMs增加蛋白結(jié)合,進(jìn)而使細(xì)胞能更耐受氧氣/葡萄糖剝奪誘導(dǎo)的細(xì)胞死亡[41]。

這些研究都說明低溫條件下miRNA有潛在的作用,其表達(dá)水平與預(yù)測(cè)的轉(zhuǎn)錄靶物表達(dá)之間的關(guān)系是相反的。哺乳動(dòng)物冬眠的情況展示了組蛋白轉(zhuǎn)錄后修飾(乙?；?、磷酸化)和組蛋白去乙酰酶抑制劑活性的改變,其潛在的基因沉默機(jī)制包括miRNA表達(dá)的改變能抑制mRNA的轉(zhuǎn)錄后翻譯和細(xì)胞核和細(xì)胞質(zhì)中核糖體蛋白質(zhì)的形成,從而在動(dòng)物再次蘇醒前起到保存mRNA轉(zhuǎn)錄本的作用[42]。

4 展 望

為了應(yīng)對(duì)各種環(huán)境壓力如冷暴露,代謝減退的自然模型表現(xiàn)出復(fù)雜的生化調(diào)控過程。miRNA可以使大量的轉(zhuǎn)錄產(chǎn)物沉默的特征使大量研究者趨之若鶩。但是研究的物種和組織部位都值得思考。

黃鼠作為典型的貯脂型冬眠動(dòng)物,其冬眠顯示出典型的季節(jié)性,對(duì)其的研究對(duì)了解人類的肥胖及與之相關(guān)的代謝性疾病有益。它在一年里不分季節(jié)地進(jìn)行多日的蟄眠,而蝙蝠家族廣泛的異溫性分類多樣性說明它是研究異溫哺乳動(dòng)物進(jìn)化史的好模型[43]。這些原因使得對(duì)這些冬眠物種的脂肪和大腦等的miRNA研究較多,而其他的例如花栗鼠等貯食型冬眠動(dòng)物在冬眠期體內(nèi)組織中miRNA的變化也是值得關(guān)注的。

對(duì)于冬眠動(dòng)物來說,WAT、BAT、肝臟、骨骼肌、腎臟和大腦等組織中miRNA都會(huì)在異溫期和恒溫期發(fā)生變化,特別是大腦等神經(jīng)系統(tǒng)的重要性是眾所周知的。在研究大腦時(shí)似乎應(yīng)該更細(xì)致些,從部位上來看,確定大腦、小腦和中縫核群等部位的miRNA表達(dá)是否有差異性;從細(xì)胞分類來看,分析神經(jīng)膠質(zhì)細(xì)胞和神經(jīng)元的miRNA表達(dá)是否有差異性。

總之,未來應(yīng)該進(jìn)行不同動(dòng)物模型體內(nèi)miRNA綜合表達(dá)的研究,從而鑒定低溫條件下miRNA的調(diào)控作用。此外,為了更好地了解低溫條件下miRNA的生化和生理功能,還應(yīng)該確定miRNA的靶物。最后,miRNA作為一個(gè)冬眠調(diào)控的信號(hào),將會(huì)是動(dòng)物應(yīng)對(duì)極端條件的一個(gè)有用的分子家族。

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Roles of microRNAs in regulation of hibernation

SONGShiyi,LIUChunyan,JIANGWen,WANGJin,ZHANGYuan

(College of Life Science, Shenyang Normal University, Shenyang 110034, China)

Hibernation is a strategy chose by many mammals to survive from harsh environmental stresses such as low temperatures, lack of food or anoxic, which is characterized by the changes of hypothermia, the low heart rate, metabolic rate and respiratory rate and so on. These processes are accompanied with the regulation from physiological and biochemical level in different tissues from different hibernators, in addition, microRNAs(miRNAs)have potential regulation effect on them. It is helpful to know the metabolism process and mechanism of miRNAs function. MiRNAs regulate glycolysis, gluconeogenesis, amino-acid metabolism, insulin signal path, fatty acid metabolism and hemeostasis of lipid metabolism in hibernators, thus, they regulate hibernating energy source changing from carbohydrates into fat. MiRNAs can protect hibernators’ brain, muscle, kidney, liver, brain and soon from low temperature and accompanying hurt and then wake up after hibernation potentially. At last, some humble proposals on miRNAs from the hibernation species and the organs and tissues of them in the future research are put forward.

mammal; hibernation; MicroRNAs; target

2016-12-01。

國家自然科學(xué)基金資助項(xiàng)目(31670425)。

宋士一(1965-),男,遼寧沈陽人,沈陽師范大學(xué)副教授,博士。

1673-5862(2017)01-0014-05

Q74; Q291

A

10.3969/ j.issn.1673-5862.2017.01.002