脂肪組織中的miRNAs研究進(jìn)展

郭云濤，張秀秀，黃萬龍，苗向陽中國農(nóng)業(yè)科學(xué)院　北京畜牧獸醫(yī)研究所，北京　100193

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脂肪組織中的miRNAs研究進(jìn)展

郭云濤，張秀秀，黃萬龍，苗向陽
中國農(nóng)業(yè)科學(xué)院北京畜牧獸醫(yī)研究所，北京100193

郭云濤, 張秀秀, 黃萬龍, 等. 脂肪組織中的miRNAs研究進(jìn)展. 生物工程學(xué)報(bào), 2016, 32(2): 151–163.

Guo YT, Zhang XX, Huang WL, et al. Recent advances of miRNAs in adipose tissues. Chin J Biotech, 2016, 32(2): 151–163.

摘 要:miRNA 是近年來發(fā)現(xiàn)的一類長約22 nt的內(nèi)源性非編碼RNA，在動物中主要通過抑制靶mRNA翻譯，在轉(zhuǎn)錄后水平調(diào)控基因表達(dá)。大量研究表明脂肪組織中的miRNAs參與了脂肪細(xì)胞分化、脂代謝等多種生物過程調(diào)控，其自身也受到轉(zhuǎn)錄因子、脂肪細(xì)胞因子和環(huán)境因子等調(diào)控，這些復(fù)雜的相互作用關(guān)系構(gòu)成了脂肪組織中miRNA的調(diào)控網(wǎng)絡(luò)，循環(huán)miRNA的發(fā)現(xiàn)為這個(gè)網(wǎng)絡(luò)加入了新元素。對肥胖等代謝疾病的研究，應(yīng)該從這個(gè)復(fù)雜的動態(tài)網(wǎng)絡(luò)中尋找答案。文中綜述了脂肪組織中miRNA的最新研究進(jìn)展，以期為利用miRNA進(jìn)行肥胖等相關(guān)代謝失調(diào)疾病的治療提供新思路。

關(guān)鍵詞:miRNA，脂肪，分化，脂代謝，循環(huán)miRNA

Received: April 9, 2015; Accepted: June 2, 2015

Supported by: The Major Science and Technology Project of New Variety Breeding of Genetically Modified Organisms (Nos. 2009ZX08008-004B, 2008ZX08008-003), National High Technology Research Development Program of China (863 Program) (No. 2008AA10Z140), National Natural Science Foundation of China (No. 30571339), the Innovation Research Foundation of CAAS (No. 2004-CAAS-1), the Basic Research Fund for Central Public Research Institutes of CAAS (Nos. 2013ywf-yb-5, 2013ywf-zd-2), the Agricultural Science and Technology Innovation Program (No. ASTIP-IAS05).

轉(zhuǎn)基因生物新品種培育科技重大專項(xiàng) (Nos. 2009ZX08008-004B, 2008ZX08008-003)，國家高技術(shù)研究發(fā)展計(jì)劃 (863計(jì)劃) (No. 2008 AA10Z140)，國家自然科學(xué)基金 (No. 30571339)，中國農(nóng)業(yè)科學(xué)院創(chuàng)新基金 (No. 2004-院-1)，中央級公益性科研院所基本科研業(yè)務(wù)費(fèi)專項(xiàng)資金項(xiàng)目 (Nos. 2013ywf-yb-5, 2013ywf-zd-2)，中國農(nóng)業(yè)科學(xué)院農(nóng)業(yè)科技創(chuàng)新項(xiàng)目 (No. ASTIP-IAS05) 資助。

網(wǎng)絡(luò)出版時(shí)間：2015-07-21網(wǎng)絡(luò)出版地址：http://www.cnki.net/kcms/detail/11.1998.Q.20150721.0839.001.html

哺乳動物體內(nèi)的脂肪組織主要分布在皮下、肌肉、腹部和內(nèi)臟等部位，由脂肪細(xì)胞、豐富的血管和神經(jīng)組成，它可以將體內(nèi)過剩的能量以甘油三酯的形式貯存下來，起著緩沖、維持體溫和貯存能量等重要作用。然而，近年來隨著人們生活水平的提高，高脂食物的過量攝入以及不良的生活習(xí)慣導(dǎo)致超重和肥胖人群的數(shù)目越來越大，究其原因是脂肪組織的過度積聚，其細(xì)胞水平的表現(xiàn)就是脂肪細(xì)胞體積增大和數(shù)目增加。肥胖引起的機(jī)體能量代謝失調(diào)導(dǎo)致了一系列相關(guān)慢性疾病如Ⅱ型糖尿病、高血壓和心腦血管疾病等的發(fā)生，已成為威脅人類健康的重大隱患。microRNA (miRNA，微RNA)是一類小分子非編碼RNA，可以在轉(zhuǎn)錄后水平調(diào)控基因表達(dá)。已有研究表明[1]，miRNA參與了脂代謝、脂肪細(xì)胞分化、能量穩(wěn)態(tài)、葡萄糖刺激的胰島素分泌和炎癥反應(yīng)等多種生物學(xué)過程，研究脂肪組織中的miRNA及其作用機(jī)制對于解決肥胖等代謝疾病有重要意義。本文綜述了脂肪組織中有代表性的miRNA在脂肪細(xì)胞分化和脂代謝中功能的最新研究，并對循環(huán)miRNA和影響脂肪組織中miRNA功能行使的因素進(jìn)行闡述，構(gòu)建了脂肪組織中miRNA的調(diào)控網(wǎng)絡(luò)，為利用miRNA進(jìn)行肥胖等相關(guān)疾病的預(yù)防和治療提供新思路。

1　miRNA簡介

miRNA是在多種真核細(xì)胞和病毒中發(fā)現(xiàn)的一類長約21–22 nt的內(nèi)源性非編碼單鏈RNA，通過特異性堿基互補(bǔ)的方式與靶基因mRNA的3'-UTR結(jié)合，抑制靶mRNA翻譯或誘導(dǎo)其降解，從而在轉(zhuǎn)錄后水平調(diào)控基因的表達(dá)。miRNA的產(chǎn)生包括以下幾個(gè)過程：1) 編碼miRNA的基因在RNA聚合酶Ⅱ的作用下轉(zhuǎn)錄形成初級轉(zhuǎn)錄本pri-miRNA；2) Pri-miRNA在Drosha/DGCR8復(fù)合體的切割下形成miRNA前體pre-miRNA；3) Pre-miRNA被Exportin5從細(xì)胞核轉(zhuǎn)運(yùn)到細(xì)胞質(zhì)；4) Pre-miRNA被Dicer酶加工成雙鏈成熟miRNA，隨后雙鏈解旋，形成單鏈成熟miRNA。miRNA的產(chǎn)生過程受到了許多轉(zhuǎn)錄因子調(diào)控，隨后成熟單鏈miRNA形成沉默誘導(dǎo)復(fù)合體RISC，抑制或者降解靶mRNA。自從第一個(gè)miRNA lin-4在線蟲中被發(fā)現(xiàn)以來，越來越多的miRNA被鑒定出來，截止到2014年6月，miRbase (http://www.mirbase.org/) 收錄的miRNA條目已達(dá)28 645條，并且數(shù)目在逐年增長。miRNA參與了各種生命過程的調(diào)控，包括細(xì)胞的增殖、分化和物質(zhì)代謝等，在生物體生長、發(fā)育和疾病發(fā)生等過程中扮演著重要角色[2]。

2　miRNA調(diào)控脂肪細(xì)胞分化

脂肪細(xì)胞由間充質(zhì)干細(xì)胞 (Mesenchymal stem cells，MSCs) 分化而來。MSCs首先經(jīng)歷細(xì)胞系定型，確定向脂肪細(xì)胞分化，隨后形成的前體脂肪細(xì)胞經(jīng)歷克隆增殖、生長停滯和終末分化形成成熟的脂肪細(xì)胞，在這一過程中pRB-E2F、MAPK、SMAD/TGFβ和WNT等關(guān)鍵信號通路以及CCAAT/增強(qiáng)子結(jié)合蛋白(CCAAT/enhancer-binding proteins，C/EBPs) 和過氧化物酶體增殖物激活受體 (Peroxisome proliferator-activated receptors，PPARs) 等核心轉(zhuǎn)錄因子發(fā)揮了重要的調(diào)控作用。2004年，Esau 等[3]發(fā)現(xiàn)miR-143可以通過其靶基因蛋白激酶5 (Mitogen-activated protein kinase 5，MAP2K5)促進(jìn)脂肪細(xì)胞分化，自此第一個(gè)影響脂肪細(xì)胞分化的miRNA被鑒定出來。隨后，越來越多的參與脂肪細(xì)胞分化miRNA如let-7、miR-17-92等被陸續(xù)發(fā)現(xiàn)，這些研究結(jié)果表明，miRNA對脂肪細(xì)胞分化調(diào)節(jié)的實(shí)質(zhì)是靶向作用于細(xì)胞分化過程中相關(guān)通路 (如pRB-E2F、MAPK、SMAD/TGFβ和WNT等) 的分子組件進(jìn)而影響下游轉(zhuǎn)錄因子轉(zhuǎn)錄活動，或者是直接作用于關(guān)鍵轉(zhuǎn)錄因子 (如C/EBPs和PPARs等)，從而轉(zhuǎn)錄調(diào)控脂肪酸結(jié)合蛋白4 (Fatty acid binding protein 4，F(xiàn)ABP4)、脂肪酸合成酶 (Fatty acid synthase，F(xiàn)ASN)、硬脂酰輔酶A去飽和酶(Stearoyl-CoA desaturase，SCD) 和葡萄糖轉(zhuǎn)運(yùn)蛋白4 (Glucose transporter 4，GLUT4) 等脂肪相關(guān)基因的表達(dá)，影響脂肪細(xì)胞分化。

miR-143是第一個(gè)發(fā)現(xiàn)的促進(jìn)脂肪細(xì)胞分化的miRNA。Esau等[3]運(yùn)用芯片技術(shù)分析了miRNA在人脂肪細(xì)胞中的表達(dá)情況，鑒定出miR-143能促進(jìn)脂肪細(xì)胞的分化，進(jìn)一步分析表明，miR-143對脂肪細(xì)胞分化的促進(jìn)作用是通過其靶基因MAP2K5實(shí)現(xiàn)的。Yi等[4]也發(fā)現(xiàn)miR-143可以通過抑制其靶基因多效生長因子(Pleiotrophin，PTN) 的表達(dá)促進(jìn)脂肪細(xì)胞分化。Takanabe等[5]用高能量飼料喂養(yǎng)構(gòu)建的肥胖小鼠模型中miR-143出現(xiàn)上調(diào)表達(dá)，導(dǎo)致小鼠體重和脂肪的增加，這些現(xiàn)象表明miR-143不僅在細(xì)胞水平參與了脂肪細(xì)胞的分化，在成體時(shí)也同樣參與了脂質(zhì)的積累調(diào)控。Chen等[6]對人脂肪基質(zhì)細(xì)胞 (Human adipose-derived mesenehymal stem cells，hADSCs) 不同分化時(shí)序中miR-143的作用進(jìn)行研究時(shí)發(fā)現(xiàn)，在不同的分化階段將miR-143轉(zhuǎn)染進(jìn)hADSCs細(xì)胞會發(fā)揮不同的作用。在有絲分裂克隆增殖階段轉(zhuǎn)染會抑制脂肪細(xì)胞分化，而在生長停滯或終末分化階段轉(zhuǎn)染時(shí)卻會促進(jìn)分化，說明miR-143對脂肪細(xì)胞分化的調(diào)控作用因分化階段不同而異。總之，miR-143可以通過MAPK信號通路中的分子組件調(diào)節(jié)脂肪細(xì)胞分化。

Wang等[7]研究發(fā)現(xiàn)，在小鼠3T3L1前體脂肪細(xì)胞分化前的克隆擴(kuò)增階段，miR-17-92簇上調(diào)表達(dá)。在激素的誘導(dǎo)下，miR-17-92過表達(dá)加速了3T3L1前體脂肪細(xì)胞分化，增加了甘油三脂積聚。后續(xù)的熒光素酶報(bào)告實(shí)驗(yàn)表明腫瘤抑制因子成視網(wǎng)膜細(xì)胞瘤樣蛋白2 (Retinoblastoma-like protein 2，Rb2/P130) 是miR-17-92的直接靶基因，在有絲分裂克隆增殖階段下調(diào)表達(dá)。siRNA介導(dǎo)的Rb2/P130抑制重現(xiàn)了miR-17-92過表達(dá)的表型。針對這些現(xiàn)象推測：在激素誘導(dǎo)后3T3L1前體脂肪細(xì)胞中，miR-17-92表達(dá)量升高，抑制了其靶基因Rb2/P130表達(dá)，致使沒有足夠的Rb2/P130與轉(zhuǎn)錄因子E2F (E2F transcription factor，E2F) 組成二聚體來抑制E2F，活化狀態(tài)的E2F4和E2F5增加，激活了pRB-E2F信號通路，啟動細(xì)胞進(jìn)入下一個(gè)周期。在另外一項(xiàng)研究中，Chen等[8]用芯片技術(shù)研究大鼠ADSCs向成熟脂肪細(xì)胞分化時(shí)miRNA的表達(dá)譜時(shí)發(fā)現(xiàn)：miR-363通過轉(zhuǎn)錄后抑制其靶基因E2F3的翻譯水平，激活了成視網(wǎng)膜瘤蛋白信號通路pRB-E2F，進(jìn)而抑制了周期蛋白E (Cyclin E，CYCE) 的表達(dá)并阻止細(xì)胞從G1向S期的轉(zhuǎn)變，從而抑制了脂肪細(xì)胞分化中的克隆增殖過程，同時(shí)也引起基因C/EBPα表達(dá)下調(diào)，抑制了細(xì)胞終末分化。miR-17-92和miR-363都通過pRB-E2F信號通路調(diào)控了脂肪細(xì)胞分化，二者的區(qū)別是前者促進(jìn)分化，后者抑制分化。

Kim等[9]在研究hADSCs向脂肪細(xì)胞分化的機(jī)制時(shí)發(fā)現(xiàn)miR-21出現(xiàn)了上調(diào)表達(dá)，過表達(dá)miR-21后hADSCs細(xì)胞的成脂分化被加強(qiáng)，抑制miR-21得到了相反的結(jié)果。進(jìn)一步的研究證明，在誘導(dǎo)成脂分化時(shí)miR-21的上調(diào)表達(dá)抑制了其靶基因轉(zhuǎn)化生長因子β受體2 (Transforming growth factor beta receptor 2，TGFβR2)，進(jìn)而降低了TGFβ/SMAD信號通路下游信號分子母系抗皮膚生長因子3 (Mothers against decapentaplegic homolog 3，SMAD3) 的磷酸化，減弱了TGFβ/SMAD信號通路對脂肪分化的抑制作用，隨后的RNAi干擾SMAD3基因表達(dá)實(shí)驗(yàn)驗(yàn)證了這一點(diǎn)。miR-21通過抑制其靶基因TGFβR2，調(diào)控了TGFβ/SMAD信號通路，是白色脂肪細(xì)胞分化的一個(gè)正調(diào)控因子。有學(xué)者利用MDI誘導(dǎo)和LiCl處理3T3L1前體脂肪細(xì)胞，分化成熟后，分別得到了WNT/β抑制和激活兩個(gè)細(xì)胞模型，然后利用芯片研究兩個(gè)細(xì)胞中差異表達(dá)miRNA，篩選出的miR-210可以通過抑制其靶基因轉(zhuǎn)錄因子TCF7L2 (Transcription factor 7-like 2，TCF7L2) 調(diào)控WNT信號通路，進(jìn)而調(diào)控脂肪生成。

miR-143、miR-17-92、miR-363、miR-21 和miR-210分別通過對MAPK、pRB-E2F、TGFβ/SMAD和WNT信號通路中的靶標(biāo)直接或間接作用調(diào)控了脂肪細(xì)胞分化，此外miR-27、miR-130、miR-146b和miR-31等通過直接靶向作用C/EBPα和PPARγ等脂肪細(xì)胞分化關(guān)鍵轉(zhuǎn)錄因子調(diào)控了這一過程，關(guān)于調(diào)控脂肪細(xì)胞分化的miRNAs的研究詳見表1。

3　miRNA調(diào)控脂代謝

2003年，Xu等[32]在研究果蠅時(shí)發(fā)現(xiàn)miR-14的缺失會導(dǎo)致三酰基甘油和二?；视退降脑黾樱源薽iRNA對脂代謝調(diào)控的作用得到肯定。脂代謝包括脂肪酸合成和分解、磷脂和膽固醇代謝等。與miRNA調(diào)控脂肪細(xì)胞分化的機(jī)制不同，miRNA對脂代謝的調(diào)控，是通過對脂代謝過程中相關(guān)的酶、轉(zhuǎn)錄因子或者對影響脂代謝的激素的調(diào)控作用實(shí)現(xiàn)的。脂代謝過程中的關(guān)鍵酶類有乙酰輔酶A羧化酶α (Acetyl-CoA carboxylase alpha，ACACA)、乙酰輔酶A羧化酶β (Acetyl-CoA carboxylase beta，ACACB)、還原型煙酰胺腺嘌呤二核苷酸磷酸(Triphosphopyridine nucleotide，NADPH)、ATP-檸檬酸裂解酶 (ATP-citrate lyase，ACLY)、FASN、肝臟甘油三酯激酶 (Hepatic triglyceride lipase，LIPC) 和SCD等，一些miRNA如miR-122可直接或間接調(diào)控這些酶類的合成，進(jìn)而影響脂代謝活動。固醇調(diào)節(jié)元件結(jié)合蛋白(Sterol-regulatory element binding proteins，SREBPs) 是脂代謝中一個(gè)重要的轉(zhuǎn)錄因子，在人類中由SREBF1和SREBF2基因編碼，對膽固醇穩(wěn)態(tài)有重要的調(diào)節(jié)作用。胰島素是機(jī)體內(nèi)唯一降低血糖的激素，同時(shí)促進(jìn)糖原、脂肪、蛋白質(zhì)合成，對脂類合成代謝有促進(jìn)作用，一些miRNA如miR-375可通過胰島素信號通路調(diào)節(jié)胰島素釋放，進(jìn)而影響脂代謝。其他的一些激素如胰高血糖素、腎上腺素、甲狀腺素等也在脂代謝中發(fā)揮調(diào)控功能。

表1　調(diào)控脂肪細(xì)胞分化的miRNAsTable 1 miRNAs in the regulation of white adipocytes differentiation

作為肝臟中表達(dá)豐度最高的miRNA，miR-122在肝臟中的的功能也是第一個(gè)被確定的，它能夠參與肝臟發(fā)育、肝臟脂肪代謝等多個(gè)生命過程。Esau等[33]研究表明miR-122缺失會導(dǎo)致ACACA、FASN等多種脂代謝相關(guān)基因的下調(diào)表達(dá)。Krutzfeldt等[34]發(fā)現(xiàn)利用antagomir-122處理小鼠后其血漿中的膽固醇水平也出現(xiàn)下降現(xiàn)象，而過表達(dá)miR-122會引起肝臟內(nèi)多種膽固醇生物合成相關(guān)基因表達(dá)上調(diào)，增強(qiáng)機(jī)體內(nèi)膽固醇的合成。miR-122可能對肝臟中膽固醇合成有促進(jìn)作用，是脂代謝的一個(gè)重要的調(diào)控元件。

多項(xiàng)研究表明，miR-33是維持細(xì)胞內(nèi)膽固醇動態(tài)平衡的關(guān)鍵轉(zhuǎn)錄后調(diào)節(jié)因子，通過對脂代謝的多個(gè)途徑產(chǎn)生影響，是最具代表性的調(diào)控脂代謝的miRNA。人類的miR-33可以分為miR-33a和miR-33b，二者僅差2個(gè)核苷酸，非常相似。miR-33a和miR-33b分別位于17號染色體SREBF2基因和22號染色體上SREBF1基因的內(nèi)含子區(qū)域，SREBF1基因編碼的SREBP1轉(zhuǎn)錄因子可以激活參與脂肪酸、磷脂和甘油三酯合成的基因FASN、SCD、ACC的表達(dá)，而SREBF2編碼的SREBP2轉(zhuǎn)錄因子調(diào)控了參與膽固醇合成和攝取的基因，如3-羥基-3-甲基戊二酰-輔酶A合成酶 (3-hydroxy-3-methylglutaryl-CoA synthase，HMGCR)、低密度脂蛋白受體(Low density lipoprotein receptor，LDLR) 和3-羥基-3-甲基戊二酰-輔酶A還原酶 (3-hydroxy-3-methylglutaryl-CoA reductase，HMGCS) 的表達(dá)。miR-33a和miR-33b可以通過對靶基因過氧化物酶體肉堿O型辛基轉(zhuǎn)移酶 (Carnitine O-octanoyltransferase，CROT)、三功能蛋白酶β亞基 (Trifunctional protein，beta subunit，HADHB) 和肉堿棕櫚?；D(zhuǎn)移酶1A (Carnitine palmitoyltransferase 1A，CPT1A) 的轉(zhuǎn)錄后抑制參與脂肪酸β氧化，通過靶基因三磷酸腺苷結(jié)合盒轉(zhuǎn)運(yùn)因子A1 (The ATP-binding cassette transporter A1，ABCA1)[35-36]調(diào)節(jié)膽固醇流出，也可以對SREBP蛋白的負(fù)調(diào)控因子如胰島素受體底物蛋白2 (Insulin receptor substrate 2，IRS2)、AMP活化蛋白激酶α1亞基 (AMP-activated protein kinase alpha 1 subunit，AMPKA1) 或AMP活化蛋白激酶α1催化亞基 (AMP-activated protein kinase alpha 1 catalytic subunit，PRKAA1)和去乙酰化酶6 (Sirtuin 6，SIRT6)[37]產(chǎn)生抑制作用。SREBP1/2和miR-33a/b四者相互協(xié)同，調(diào)控了脂肪酸、甘油三酯和膽固醇的穩(wěn)態(tài)[38-41]。

ABCA1蛋白是控制巨噬細(xì)胞膽固醇流出的重要調(diào)控者，可以防止膽固醇在細(xì)胞內(nèi)的過量積累。Ramirez等[42]在研究高脂飲食的小鼠腹膜巨噬細(xì)胞膽固醇流出時(shí)，發(fā)現(xiàn)miR-758出現(xiàn)了下調(diào)表達(dá)，肝臟中也出現(xiàn)了相同的現(xiàn)象。在小鼠和人類的體外培養(yǎng)細(xì)胞中，miR-758 能夠抑制ABCA1基因，降低其表達(dá)水平。使用anti-miR-758處理細(xì)胞則發(fā)現(xiàn)這一miRNA的抑制會導(dǎo)致ABCA1表達(dá)的增加，隨后的熒光素酶報(bào)告試驗(yàn)證實(shí)ABCA1是miR-758的直接靶基因。在小鼠細(xì)胞中，miR-758能夠減少細(xì)胞內(nèi)膽固醇流向載脂蛋白A1 (Apolipoprotein A1，APOA1)，而anti-miR-758 的應(yīng)用則會促進(jìn)膽固醇的流出。由此可知，miR-758 具有調(diào)節(jié)細(xì)胞內(nèi)膽固醇水平的能力。

miR-370 通過上調(diào)miR-122 的表達(dá)間接促進(jìn)脂類合成，還可以通過抑制其靶基因CPT1A的表達(dá)，降低脂肪酸β-氧化的速率[43]。此外，miR-27[44-46]、miR-30c[47]、miR-168a[48]、miR-223[49]、miR-302a[50]和miR-378[51]也可以對脂代謝產(chǎn)生調(diào)控作用。

4　脂肪組織中的循環(huán)miRNA

循環(huán)miRNA (Circulating miRNA) 存在于微囊泡、高密度脂蛋白復(fù)合體 (High-density lipoproteins，HDLs) 和RNA誘導(dǎo)的沉默復(fù)合體中，可以在同一組織不同細(xì)胞間和不同組織的細(xì)胞間充當(dāng)相互交流的媒介。脂肪細(xì)胞能夠分泌含有循環(huán)miRNA和細(xì)胞特異性蛋白標(biāo)志物的微囊泡，約7 000種脂肪組織特異性mRNA和140種miRNA存在于小鼠脂肪細(xì)胞系分泌的微囊泡中[52]。研究發(fā)現(xiàn)，脂肪組織細(xì)胞間傳遞的循環(huán)miRNA參與了脂類合成和細(xì)胞生長過程[53]，亦可調(diào)節(jié)脂肪細(xì)胞的脂質(zhì)積累和細(xì)胞大小[54]。

在研究miRNA在脂肪組織中的功能時(shí)，發(fā)現(xiàn)一些miRNA如miR-130b[55]可以充當(dāng)脂肪細(xì)胞和肌肉細(xì)胞之間交流的媒介。在這項(xiàng)關(guān)于肥胖的研究中，患者的TGFβ基因表達(dá)升高，刺激前體和成熟脂肪細(xì)胞分泌miR-130b，隨后miR-130b進(jìn)入血液后被運(yùn)輸?shù)郊∪饨M織，靶向抑制肌肉細(xì)胞激活物受體γ共活化劑1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha，PGC1α) 基因表達(dá)，而PGC1α在肌肉中起到脂質(zhì)氧化作用，脂肪細(xì)胞通過分泌miR-130b抑制了肌肉中的脂質(zhì)氧化。Vickers等[56]發(fā)現(xiàn)，巨噬細(xì)胞等外圍組織分泌的內(nèi)源性的miRNA如miR-223、miR-135a* 和miR-375等能夠被組裝進(jìn)HDLs中，這個(gè)過程受到神經(jīng)酰胺生物合成的限速酶中性鞘磷脂酶2 (Neutral sphingomyelinase 2，nSMase2/SMPD3) 和ABCA1的調(diào)控。隨后，組裝好的HDLs經(jīng)由經(jīng)典的膽固醇反向轉(zhuǎn)運(yùn)通路 (Reverse cholesterol transport，RCT) 進(jìn)入到肝細(xì)胞中，清道夫B族受體成員1 (Scavenger receptor class B member 1，SRB1) 參與了這一過程。HDLs進(jìn)入到肝細(xì)胞后，其中的循環(huán)miRNA通過對細(xì)胞中靶基因的抑制發(fā)揮調(diào)控作用。

循環(huán)miRNA一般以內(nèi)分泌或者旁分泌的形式發(fā)揮作用，只是對靶細(xì)胞轉(zhuǎn)錄本產(chǎn)生非特異性修飾作用，而一般的內(nèi)分泌激素如胰島素等是對靶標(biāo)的特異性的有力調(diào)控，故利用循環(huán)miRNA作為肥胖等代謝疾病治療靶點(diǎn)的作用有限，但是可以利用它作為病理狀態(tài)的標(biāo)志物。目前，多種循環(huán)miRNA已經(jīng)被用到病理狀態(tài)的診斷上，如miR-122和脂肪肝[57]、miR-223和動脈粥樣硬化[56]、miR-101/miR-375/miR-802和Ⅱ型糖尿病[58]以及l(fā)et-7e和高血壓[59]等。循環(huán)miRNA具有作為脂肪代謝相關(guān)疾病標(biāo)志物的潛能，這種新的miRNA的存在和調(diào)控方式的發(fā)現(xiàn)為脂肪組織中相關(guān)的病理研究指明了方向。

5　脂肪組織中的miRNA受到多種因素調(diào)控

脂肪組織可以分泌腫瘤壞死因子α (Tumor necrosis factor α，TNFα)、白細(xì)胞介素6 (Interleukin-6，IL-6)、抵抗素 (Resistin，RSTN)、瘦素 (Leptin，LEP) 和脂聯(lián)素 (Adiponectin，ADPN) 等脂肪細(xì)胞因子，這些細(xì)胞因子介導(dǎo)了肥胖引起的胰島素抵抗以及炎癥反應(yīng)。脂肪組織中的miRNAs在生成時(shí)候除了受到轉(zhuǎn)錄因子調(diào)控[60]之外，還受到脂肪細(xì)胞因子調(diào)控。TNFα處理前體脂肪細(xì)胞，引起了miR-143和miR-103的下調(diào)[61]，二者都是重要的脂肪生成調(diào)控者，miR-143的表達(dá)也受到脂肪組織中游離脂肪酸和脂肪細(xì)胞因子的調(diào)控[62]。此外miR-99、miR-146b、miR-155、miR-221、miR-325、miR-335和miR-378都受到了脂肪細(xì)胞因子的調(diào)控[22,26,63-66]，它們在成脂分化、脂質(zhì)代謝和胰島素抵抗中發(fā)揮著重要的調(diào)節(jié)作用。除此之外，脂肪組織中的miRNA還受到一些調(diào)控蛋白如KH型剪接調(diào)控蛋白(KH-type splicing regulatory protein，KSRP)、骨形態(tài)發(fā)生蛋白2 (Bone morphogenetic protein 2，BMP2) 的影響。KSRP是一種RNA結(jié)合蛋白，通過促進(jìn)miR-145形成抑制了脂質(zhì)分解[67]，BMP2通過上調(diào)MSCs中的miR-24-1和miR-31的表達(dá)調(diào)控了前體脂肪細(xì)胞增殖[68]。另外內(nèi)環(huán)境葡萄糖濃度以及飲食[19]也影響了miRNA表達(dá)，相關(guān)的機(jī)制暫不清楚?？傊?，脂肪組織中的miRNA的表達(dá)水平受到了轉(zhuǎn)錄因子、脂肪細(xì)胞因子、調(diào)控蛋白和一些理化因素的調(diào)控，維持在一個(gè)相對穩(wěn)定的狀態(tài)。

6　展望

近年來，由于肥胖及其并發(fā)癥等發(fā)病率的飆升，miRNA在脂肪組織中功能的研究也越來越多，通過對這些研究進(jìn)行歸納，所采用的思路大致都是：首先利用高通量測序或者芯片技術(shù)篩選影響脂肪細(xì)胞分化過程中或者脂代謝過程中的miRNA，然后利用生物信息學(xué)手段預(yù)測其靶基因并進(jìn)行雙熒光素酶報(bào)告實(shí)驗(yàn)證實(shí)靶基因，繼而在3T3L1或者M(jìn)SC細(xì)胞中對目標(biāo)miRNA進(jìn)行干擾或過表達(dá)，觀察細(xì)胞分化狀態(tài)變化和脂質(zhì)積聚情況，最后在動物水平觀察抑制或過表達(dá)模型。在實(shí)驗(yàn)第一步手段的選擇上，高通量測序愈來愈受到青睞，歸其原因主要是在測序成本的逐年降低和測序技術(shù)本身的優(yōu)勢如準(zhǔn)確定量和新miRNA的鑒定等，利用二代測序技術(shù)對miRNA進(jìn)行研究已經(jīng)成為一個(gè)主要的方法。本實(shí)驗(yàn)室前期對不同脂肪沉積能力的兩個(gè)牛種皮下脂肪組織進(jìn)行了Illumina測序，獲得了17個(gè)差異表達(dá)miRNA，通過對這些差異表達(dá)miRNA的預(yù)測靶基因進(jìn)行功能和信號通路富集分析表明這些miRNA可能通過PPARα等靶基因，參與了脂肪酸代謝等生物學(xué)過程和PPAR等信號通路，調(diào)控了脂肪細(xì)胞分化和脂代謝，進(jìn)而影響了牛脂肪沉積。牛脂肪沉積機(jī)制的研究有望鑒定出影響脂肪細(xì)胞分化和脂代謝過程的調(diào)控分子，對肥胖等人類疾病研究也有理論意義。

在生物體內(nèi)，一個(gè)miRNA可能作用于多個(gè)靶基因，也可能是多個(gè)miRNA調(diào)控一個(gè)靶基因，這種作用構(gòu)成一個(gè)調(diào)控網(wǎng)絡(luò)，在某些信號的刺激下，從整體上調(diào)控有機(jī)體的生命活動，因此miRNA的作用是通過其復(fù)雜的靶基因協(xié)同調(diào)節(jié)實(shí)現(xiàn)的。miRNA通過對其靶基因的抑制作用調(diào)控了脂肪細(xì)胞分化和脂代謝相關(guān)的復(fù)合體和信號通路 (圖1)，同時(shí)它受到許多上游轉(zhuǎn)錄因子以及細(xì)胞因子等調(diào)節(jié)。轉(zhuǎn)錄因子、環(huán)境因素、miRNA和下游靶基因及其所在的信號通路，形成了一個(gè)復(fù)雜的調(diào)控網(wǎng)絡(luò)，調(diào)控了機(jī)體前體脂肪細(xì)胞分化和脂代謝[69]，miR-130b等循環(huán)miRNA的發(fā)現(xiàn)又增加了這個(gè)調(diào)控網(wǎng)絡(luò)的復(fù)雜性 (圖2)。

圖1　miRNA調(diào)控脂肪細(xì)胞分化和脂代謝的機(jī)制Fig. 1 The regulation mechanism of miRNAs in adipocyte differentiation and lipid metabolism.

圖2　脂肪組織中的miRNAs調(diào)控網(wǎng)絡(luò)Fig. 2 The regulating network of miRNAs in adipose tissues.

目前對肥胖和相關(guān)代謝失調(diào)疾病治療的研究聚焦在一些易受到藥物影響的酶類上面，如降膽固醇藥物可以通過HMGCR降低血液膽固醇含量。對脂肪組織中miRNA的研究表明一些miRNA可以對脂肪細(xì)胞分化和脂代謝產(chǎn)生重要影響，有成為治療靶點(diǎn)的潛能。然而，鑒于miRNA與其靶基因的作用以及生物過程時(shí)序的復(fù)雜性等，這個(gè)龐大的調(diào)控網(wǎng)絡(luò)遠(yuǎn)遠(yuǎn)沒有研究透徹，將miRNA應(yīng)用于臨床治療尚有諸多難點(diǎn)。最近成人體內(nèi)功能性棕色脂肪的發(fā)現(xiàn)為肥胖等代謝疾病的研究帶來了契機(jī)，miR-133[70]等參與棕色脂肪細(xì)胞分化調(diào)節(jié)的miRNA被鑒定出來，利用miRNA治療肥胖等疾病有望在棕色脂肪細(xì)胞分化方面取得突破。另外，針對肥胖以及肥胖相關(guān)并發(fā)癥的治療，不應(yīng)僅局限于miRNA，其上游的轉(zhuǎn)錄因子、下游的靶基因、調(diào)控蛋白和環(huán)境理化因素亦具有成為治療靶標(biāo)的潛能。對脂肪細(xì)胞分化乃至肥胖等的研究應(yīng)該在這個(gè)動態(tài)的網(wǎng)絡(luò)中尋找答案，對脂肪組織中miRNA的功能研究，也可借鑒Calura等[71]在通路中研究miRNA作用機(jī)制的方法，結(jié)合上游轉(zhuǎn)錄因子、細(xì)胞因子、表型相關(guān)的靶基因所在通路，甚至代謝組、蛋白質(zhì)組等，繪制miRNA參與的調(diào)控網(wǎng)絡(luò)，在網(wǎng)絡(luò)中發(fā)現(xiàn)關(guān)鍵的基因或代謝途徑。隨著調(diào)控脂肪細(xì)胞分化研究的深入，人們對這個(gè)復(fù)雜的調(diào)控網(wǎng)絡(luò)的了解越來越透徹，相信在不久的將來一定能夠研究出更加有效的治療肥胖的藥物或方法。

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數(shù)字出版從概念的誕生，到逐步發(fā)展壯大，由最初的2009年799.4億元的年產(chǎn)值，增長至2017年的7071.93億元年產(chǎn)值（如圖1所示），從數(shù)值上看，是一個(gè)高速增長的產(chǎn)業(yè)。先后經(jīng)歷了爆發(fā)式增長、高速增長階段的中國數(shù)字出版業(yè)，下一階段，正走向高質(zhì)量發(fā)展的康莊大道。

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(本文責(zé)編郝麗芳)

Recent advances of miRNAs in adipose tissues

Yuntao Guo, Xiuxiu Zhang, Wanlong Huang, and Xiangyang Miao
Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China

Abstract:microRNAs (miRNAs), a class of endogenous non-coding RNA about 22 nucleotide long, regulate gene expression at the post-transcription level by inhibiting the translation or inducing the degradation of their target mRNAs inorganisms. A lot of studies reveal that miRNAs in adipose tissues are involved in adipocyte differentiation and lipid metabolism and modulated by multiple transcription factors, adipocytokines and environmental factors, which form a complex regulatory network maintaining the homeostasis of adipose tissues. The discovery of circulating miRNAs adds new elements to the regulatory network. To study the metabolic diseases such as obesity, we should keep a new insight into the complex dynamic network. In this review, we summarize the latest studies of miRNAs in adipose tissues, which might provide new strategies for the treatment of obesity and other related diseases.

Keywords:miRNA, adipose, differentiation, lipid metabolism, circulating miRNA

Corresponding author:Xiangyang Miao. Tel: +86-10-62895663; E-mail: mxy32@sohu.com