胆固醇是一种环戊烷多氢菲的衍生物，溶解性与脂肪类似，以游离和胆固醇脂的形式存在，主要通过肝脏合成，其次是食物摄取[1]；肠道转运时间与胆固醇吸收呈负相关，转运时间越慢，吸收率越高[2]。肝脏通过控制胆固醇生物合成与产生脂蛋白并结合胆固醇转运、摄取及转化为胆汁酸排泄等方式，维持机体胆固醇稳态[3-4]。
microRNA(miRNA)是内源性的、非编码蛋白质、分子量小的RNA(18~25个核苷酸)，进化上具有高度保守性，几乎存在于所有生物体内的各种组织中[5]。miRNA分为蛋白质编码的内含子型miRNA和非蛋白质编码的miRNA，非蛋白编码的miRNA一般位于编码基因的外围，占绝大多数；也有一部分miRNA成簇地排列在染色体上，且可协同表达[6]。miRNA可以调节参与同一细胞途径或生理过程的多个mRNA的表达，同一个mRNA也可以被多个miRNA调控。miRNA可通过抑制胆固醇合成、转运与分解相关基因表达与翻译，并参与不同组织之间协同调控，且可稳定地在血液中被运输[7]。
1 miRNA调控mRNA机制miRNA通过特异性互补结合mRNA序列的3′非翻译区(3′ untranslated regions, 3′UTR)，抑制靶mRNA转录和翻译[8]，甚至降解靶mRNA[9]。miRNA调控mRNA具体机制如下：miRNA通过RNA聚合酶Ⅱ被转录成一个具有几千个碱基对的双链茎环结构原代miRNA(primary miRNA, pri-miRNA)，pri-miRNA进一步被Drosha-DGCR8复合酶处理形成(precursor RNA, pre-miRNA；60~70个核苷酸)[10]。exportin 5蛋白可识别pre-miRNA，将pre-miRNA从细胞核运输到细胞质中，pre-miRNA被核酸内切酶Dicer切割成18~25个核苷酸的双链miRNA，双链miRNA随后在DGCR8蛋白的激活下被打开，其中的一条链随即被降解，为过客链(passenger strand)，另一条成熟的miRNA链为引导链(guide strand)。DGCR8蛋白与成熟的miRNA结合到RNA诱导的沉默复合物(RNA induced silencing complex，RISCs)中，RISCs含有裂解mRNA的降解酶[11]。miRNA通过3种方式调控靶基因：1)若靶基因的3′UTR靶序列区与miRNA精确互补，则mRNA转录被抑制；2)若靶基因靶序列区与miRNA为不完全互补，则mRNA翻译被抑制；3)以上2种方式同时对靶基因抑制[12-13]。
2 miRNA调控胆固醇合成代谢哺乳动物细胞存在3种固醇调节元件结合蛋白(sterol regulatory element binding protein, SREBP)的亚型，分别为SREBP1a、SREBP1c及SREBP2。SREBP1c受胰岛素、氧化甾醇和磷脂酰胆碱的调节，优先促进脂肪酸、磷脂和三酰甘油合成相关基因的转录；SREBP2和SREBP1a则调节细胞内胆固醇稳态[14]。SREBP由1个与膜定位调节域相连的氨基末端转录因子域组成，并由2个紧密相连的膜疏水螺旋将前体SREBP以发夹的方式排列在内质网和核膜上，这2个螺旋由1个31-氨基酸亲水环分开，该亲水环伸入内质网的内腔；SREBP氨基末端片段包含基本螺旋环螺旋亮氨酸拉链结构和转录激活域，并与其裂解活化蛋白(SREBP cleavage-activating protein, Scap)形成复合物[1]。正常情况下，SREBP蛋白以非活性形式与Scap结合于内质网中，Scap是一种内质网结合的细胞质蛋白，作为监测细胞固醇水平的传感器[15]。当SREBP被激活，可释放其N端并进入核内，与固醇调节元件结合并调控下游基因[16]。SREBP2是胆固醇生物合成和摄取的主要调节因子，其蛋白控制刺激细胞胆固醇摄取和合成程序。SREBP2的前体穿插于细胞内质网膜内外，其氨基端和羧基端的功能结构域暴露于细胞质中，当SREBP1c基因被敲除，会导致SREBP2表达和蛋白表达增加，说明SREBP1c反向调节SREBP2的表达[14]。miRNA-185对SREBP2转录调控迅速，当miRNA-185被过度表达，SREBP2的表达也迅速减弱[17]。当细胞胆固醇含量较高的情况下，miRNA-185可抑制SREBP2基因的表达，使胆固醇从头合成相关基因表达降低，低密度脂蛋白受体(low density lipoprotein receptor，LDLR)蛋白和低密度脂蛋白(low density lipoprotein LDL)摄取减少；同时，miRNA-185可被SREBP1c转录激活，负调控SREBP2的表达，且miRNA-4644和miRNA-4306被认为与miRNA-185具有相同的3′UTR序列[18]。
Vickers等[19]发现，miRNA-223可直接靶向并抑制2个胆固醇生物合成基因——3-羟基-3-甲基戊二酰辅酶A合成酶1(3-hydroxy-3-methylglutaryl coenzyme A synthase 1, HMGCS1)和甾醇C4甲基氧化酶(sterol-C4-methyl oxidase-like, SC4MOL)表达。SC4MOL基因的功能缺失会导致胆固醇生物合成的丧失，降低胆固醇合成效率[20]。胆固醇合成的第1步是由HMGCS1介导，该基因编码3-羟基-3-甲基戊二酰辅酶A(3-hydroxy-3-methylglutaryl coenzyme A, HMG-CoA)，将乙酰辅酶A转化为HMG-CoA[21]。3-羟基-3-甲基戊二酰辅酶A还原酶(3-hydroxy-3-methylglutaryl coenzyme A reductase, HMGCR)是肝脏胆固醇合成过程中的限速酶，通过催化HMG-CoA转化为甲羟戊酸，控制胆固醇合成[22]。HMGCR的C端(起催化作用)位于细胞质内，8个穿膜区上的N端将该酶结合于胞内的内质网上。当肝细胞胆固醇含量较高时，SREBP2可激活促进细胞中胆固醇外排；当细胞中胆固醇含量较低时，SREBP2前体从内质网转移到高尔基体，在高尔基体中，SREBP2前体被加工成成熟的核形式，启动HMG-CoA与HMGCR的转录，提高肝细胞对胆固醇合成及摄取[14]。HMGCR除了直接调控胆固醇合成外，该基因表达量与细胞内胆固醇含量变化存在反馈调节[22]。Sun等[23]以非酒精性脂肪肝细胞模型进行体外试验，通过荧光素酶分析发现，HMGCR是miRNA-21的直接靶点，miRNA-21对HMGCR转录降解且阻碍其蛋白质翻译，导致胆固醇合成量降低。Selitsky等[24]在人肝癌细胞中证实，miRNA-21和miRNA-27均可显著抑制人肝癌细胞对胆固醇合成，分别抑制了约30%和70%；且miRNA-27通过靶向调节HMGCR的基因转录来抑制胆固醇合成，并认为miRNA-27可能在HMGCR内，甚至在其开放阅读框内。
3 miRNA调控胆固醇转运代谢脂蛋白在肝脏中合成，经卵磷脂胆固醇酰基转移酶催化，并形成胆固醇酯的方式运载胆固醇，主要为高密度脂蛋白(high density lipoprotein, HDL)、LDL、极低密度脂蛋白(very low lipoprotein, VLDL)。HDL可与胆固醇结合为高密度脂蛋白胆固醇(high density lipoprotein cholesterol, HDL-C)，并从肝脏以外组织转运到肝脏进行再循环，或以胆汁酸的形式排泄[25]；LDL和VLDL则通过结合胆固醇生成低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)和极低密度脂蛋白胆固醇(very low density lipoprotein cholesterol, VLDL-C)，运载胆固醇进入肝细胞外周血液及组织细胞，而VLDL运载的胆固醇颗粒相比LDL较大，且数量较少，不易通过动脉内膜[26-27]。
肝X受体(liver X receptor, LXR)是胆固醇转运的重要调节因子，包括LXRα和LXRβ，当SREBP2被敲除，LXR蛋白表达量与活性降低[28]，LXR可特异性地被氧甾醇、氧化型胆固醇及胆固醇合成途径的中间产物激活[29]。有研究表明，敲除小鼠LXR基因会导致胆固醇在肝脏中积累，而加入合成的LXR启动剂则能促进胆固醇从肝脏转运。LXR不但可增加ATP结合盒转运体G1(ATP-binding cassette transporter G1, ABCG1)蛋白数量，还可将ABCG1从细胞内位置重新分布到质膜[30]。ABCG1介导胆固醇与HDL结合，将胆固醇从肝脏外周组织转运到肝脏中再循环，或形成胆汁酸，这一过程称为胆固醇逆向转运(reverse cholesterol transport, RCT)，由于胆固醇不能在细胞内降解，RCT是确保体内胆固醇平衡的必要过程[31]，RCT运输胆固醇的过程涉及清道夫受体B类Ⅰ型(scavenger receptor class B type Ⅰ, SR-BⅠ)介导的HDL-C选择性脂质摄取，肝脏SR-BⅠ表达上调可加速HDL-C在血液中清除[32]。细胞质膜是ABCG1促进细胞中胆固醇与HDL结合向外排的主要部位，ABCG1可通过扩散或碰撞机制将胆固醇从质膜的内小叶转移到外小叶，转移到细胞外胆固醇受体[33]。卵磷脂胆固醇脂酰转移酶(lecithin cholesterol acyltransferase, LCAT)可介导胆固醇酯化与HDL颗粒重塑，促进胆固醇从外周组织向血液运输[34]，HDL通过胆固醇酯转移蛋白介导的转移途径间接将HDL转移到载脂蛋白B(apolipoprotein B, ApoB)，并输送到肝脏[35]。LXR能激活细胞中ATP结合盒转运蛋白A1(ATP-binding cassette protein A1, ABCA1)，ABCA1是ATP结合盒转运蛋白膜转运体家族的一类胞膜蛋白，介导HDL颗粒形成，是脂质从细胞向载脂蛋白转移的关键调节因子，在HDL的形成中起着关键作用[36-37]。载脂蛋白A-Ⅰ(apolipoprotein A-Ⅰ, ApoA-Ⅰ)是HDL的主要蛋白成分，ApoA-Ⅰ/ABCA1反应体系包括3个步骤：首先，ApoA-Ⅰ的一个小的调节池与ABCA1结合，从而促进磷脂向质膜外小叶的净转运，导致磷脂双层的2个小叶的侧向堆积密度不均匀；然后，通过弯曲和产生囊外脂质结构域来减轻膜应变，高弯曲膜表面的形成促进了ApoA-Ⅰ与这些结构域的高亲和力结合；最后，这个结合的ApoA-Ⅰ池溶解外泡结构域，以产生盘状新生的高密度脂蛋白颗粒。这些颗粒含有2、3或4个ApoA-Ⅰ分子和1个膜磷脂类补体以及一些胆固醇[38]。
SREBP2不但介导胆固醇生物合成基因表达，并同时抑制前蛋白转化酶枯草溶菌素9(proprotein convertase, subtilisin/kexin type 9, PCSK9)蛋白表达，而PCSK9可促进LDL及VLDL降解因子表达，降低血浆LDL及VLDL含量[28, 39]。LXR不但协同SREBP1c因子并提高肝脏对VLDL合成和分泌[40]，而且LXR可通过调控LDLR与细胞内胆固醇结合，控制稳态组织胆固醇浓度[41]。
miRNA在调节胆固醇转运的多个步骤中的发挥作用。miRNA参与调控RCT的大部分步骤，包括HDL的生物合成、肝细胞对HDL-C的摄取、胆汁酸的合成和分泌等[10]。已被证实，多种miRNA负调控载脂蛋白因子转录。HDL可通过结合二价阳离子转运内源性miRNA[42]，且SREBP转录因子可刺激miRNA-33a/b的表达，表明机体部分miRNA与其靶基因存在一定的反馈关系[43]。
3.1 miRNA调控HDL代谢miRNA-33主要有miRNA-33a与miRNA-33b，其分别位于人体SREBP2和SREBP1基因的内含子中，两者具有相同的种子序列，只有2个核苷酸不同[44]，而小鼠、鸡等动物由于miRNA-33b编码区部分缺失，miRNA-33b不能表达，只存在miRNA-33a[45]；miRNA-33a/b均可在鱼类中表达，且表达量较低，其被认为在鱼类调控胆固醇代谢中不起主导作用[46]。miRNA-33a和miRNA-30b可与LXR靶基因ABCA1和ABCG1的3′UTR序列互补结合，抑制ABCA1和ABCG1表达，控制胆固醇稳态[47-48]。ABCA1是HDL合成及结合胆固醇排出的调控因子，它的3′UTR长度超过3 000 bp，包括许多miRNA结合位点，已知其存在3个与miRNA-33高度保守的结合靶位点互补区域，在人和小鼠肝细胞和巨噬细胞中过表达miRNA-33，可抑制ABCA1的mRNA表达，且抑制胆固醇与ApoA-Ⅰ和HDL结合[45, 49]。当抑制miRNA-33a/b表达，能提高肝脏ABCA1基因的表达，使血浆HDL含量显著提高，促进胆固醇向肝脏转运[50-51]。也有学者发现，miRNA-33a和miRNA-10b不仅调节ABCA1，而且可靶向ABCG1(仅在小鼠中)，并增强这些miRNA对HDL-C代谢和RCT的影响[45, 50]。当细胞中胆固醇含量降低时，miRNA-758可以通过抑制ABCA1表达，保留神经中的胆固醇[52]，miRNA-182和miRNA-183也通过影响核SREBP的积累来控制胆固醇的稳态[53]。
miRNA-223可通过抑制SREBP2转录来控制胆固醇稳态。当胆固醇缺乏，miRNA-223转录和表达降低，且抑制miRNA-223可减轻肝细胞对胆固醇生物合成和摄取的抑制，并防止胆固醇与HDL结合形成HDL-C，提高细胞胆固醇含量[19]。除了控制胆固醇的生物合成，在人类中，miRNA-223还通过控制靶向SR-BⅠ的3′UTR的表达来抑制HDL-C的摄取[19]，且SR-BⅠ可被miRNA-185靶向调节，但具体机制仍不明确。除此之外，miRNA-223还参与机体炎症反应，并与大部分炎症标志物因子呈正相关[54]。
3.2 miRNA调控LDL代谢miRNA-130b和miRNA-301b位于人类22号染色体上一个与总胆固醇和HDL-C水平异常相关的位点上。这2个miRNA共享相同的种子序列，并被预测以相同的代谢因子为靶点，2种miRNA都直接靶向LDLR和ABCA1的3′UTR，从而显著降低了人肝癌细胞和小鼠巨噬细胞中LDL-C的摄取和与ApoA-Ⅰ的结合以及胆固醇的流出[55]。miRNA-148a直接作用于LDLR的3′UTR，miRNA-148a过表达和抑制分别显著降低和提高小鼠肝脏LDLR表达[17]。SREBP2可控制PCSK9的表达，而PCSK9可通过降解可介导LDLR转录来控制LDL-C代谢[41]；与miRNA-185相似，LXR介导的SREBP1c诱导导致miRNA-148a表达量增加。miRNA-128-1通过直接靶向LDLR和ABCA1的3′UTR调控人肝癌细胞和小鼠巨噬细胞胆固醇向ApoA-Ⅰ的流出[55]。
3.3 miRNA调控VLDL代谢miRNA-122和miRNA-30c是人体内通过控制VLDL分泌和胆固醇生物合成而改变血浆LDL-C的miRNA，且miRNA-122在物种间高度保守[56]。miRNA-122a和miRNA-122b这2种亚型均存在于虹鳟鱼中，而人与鼠只存在单一亚型miRNA-122a[57-58]；此外，miRNA-122在虹鳟和高等脊椎动物肝脏中特异性表达，且表达量都很高[59]。Chang等[60]认为人和鼠中miRNA-122靶基因是阳离子氨基酸转运载体1(cationic amino acid transporter 1, CAT1)，但Cirera等[61]用高胆固醇饲粮饲喂哥廷根小型猪的研究发现，肝脏miRNA-122表达量下降，但CAT1表达量无显著差异。
miRNA-30c通过直接靶向微粒体甘油三酯转移蛋白减少脂质合成和ApoB的分泌来控制血浆胆固醇水平[62]。Jeon等[53]发现，miRNA-182和miRNA-96可分别靶向F-box和WD重复结构域7(F-box and WD repeat domain-containing7, Fbxw7)和胰岛素诱导基因2(insulin-induced gene 2, INSIG2)的抑制表达，这2种蛋白限制细胞核SREBP积累，INSIG2降低细胞膜膜结合SREBP前体的蛋白水解酶活性，Fbxw7是E3泛素连接酶，通过蛋白酶体靶向核中SREBP的转换。
4 miRNA调控胆固醇分解代谢胆固醇是构成细胞膜的成分，可通过调控细胞膜流动性来维持细胞膜稳定，同时也是胆汁酸、性激素、维生素D及肾上腺皮质激素等机体生理活性物质的重要合成原料[63]。胆固醇可分解为胆汁酸参与机体脂代谢，且胆汁酸完全由肝脏中的胆固醇合成。胆汁酸合成速率主要受胆固醇7α-羟化酶(cholesterol 7alpha-hydroxylase, CYP7A1)转录调控，CYP7A1是编码胆汁酸合成途径中的限速酶，此酶活性增加会导致胆固醇分解代谢加快，从而降低细胞内胆固醇含量[64]；除此之外，胆汁酸另一个合成途径限速酶为甾醇27羟化酶(sterol 27-hydroxylase, CYP27A1)[65]。在鼠的研究中发现，CYP7A1是miRNA-33a的靶基因，miRNA-33a可作为一种快速反馈机制靶向抑制CYP7A1的翻译，且CYP7A1可通过将肝脏过量的胆固醇转化为胆汁酸，并反馈激活SREBP2和miRNA-33a，在感知和维持胆固醇稳态方面起主导作用[66]。
Tao等[67]对罗非鱼miRNA和mRNA基因组进行测序分析发现，miRNA-21与miRNA-200b负调控细胞色素P450家族11亚科A成员1(cytochrome P450 family 11 subfamily A member 1，CYP11A1)，CYP11A1可将胆固醇转化为孕烯雌酮，并参与机体类固醇激素合成。
5 小结miRNA可通过对胆固醇合成、转运、分解相关靶基因表达进行负调控，且可在血液中被运输。miRNA可以调节参与同一细胞途径或生理过程的多个mRNA的表达，同时，同一个mRNA也可被多个miRNA调控，且miRNA表达与靶基因存在反馈调节。由于动物种属间差异，其miRNA表达量也不同，且存在同一miRNA的不同亚型分别调控同一靶基因的不同亚型的现象，甚至某些动物miRNA亚型缺失。这使得miRNA与靶mRNA调控关系更加复杂，其靶向关系与功能研究尤为重要。
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