2020, Vol. 36中国科学院微生物研究所、中国微生物学会主办
文章信息
- 何春, 张琦悦, 孙浩玮, 蔡瑞, 庞卫军
- He Chun, Zhang Qiyue, Sun Haowei, Cai Rui, Pang Weijun
- miRNA和lncRNA在动物脂肪沉积中的研究进展
- Role of miRNA and lncRNA in animal fat deposition-a review
- 生物工程学报, 2020, 36(8): 1504-1514
- Chinese Journal of Biotechnology, 2020, 36(8): 1504-1514
- 10.13345/j.cjb.200232
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文章历史
- Received: April 24, 2020
- Accepted: May 21, 2020
- Published: June 16, 2020
引用本文
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脂肪沉积是指机体将过多摄入的能量储存在脂肪组织中这一过程，脂肪组织可以在适宜的时候释放能量，用于维持机体能量代谢平衡。除此之外，脂肪也是机体中很多脂溶性维生素和类固醇激素的重要来源，还具有高度活跃的分泌功能，能分泌一系列脂肪细胞因子调节机体代谢[1]。同时，在畜牧业上，脂肪沉积还会影响畜禽的产肉量与肉品质[2-3]。而脂肪功能的异常不仅会引发一系列的代谢综合征，还会影响脂肪在体内的沉积，导致机体过瘦或过肥，增加患病风险。在过去的几年中，越来越多的研究表明，曾被认为是基因组“噪音”的miRNA和lncRNA可以通过参与脂肪沉积调控网络，介导脂肪沉积相关基因的表观遗传、转录水平和转录后水平调控[4-6]，因此研究脂肪沉积与miRNA及lncRNA的关系，可为探索动物脂肪沉积的分子调控机制提供新的思路和方向。
1 脂肪沉积过程及其调控因子 1.1 脂肪沉积过程概述脂肪细胞作为脂肪组织的最小单位，动物的脂肪组织由大量的脂肪细胞不断聚集形成。脂肪细胞的分化过程分为定向分化和终末分化两个阶段[7]：第一阶段，多能干细胞经过定向分化形成前体脂肪细胞，前体脂肪细胞中开始出现少量的小脂滴；第二阶段，前体脂肪细胞进一步分化为球形或椭球形的多室脂肪细胞，多室脂肪细胞里有大量小脂滴，此时的细胞一般不具有分裂增殖能力，但可通过不断摄取体内游离的脂肪酸，使小脂滴不断膨大形成大脂滴，最终形成成熟的脂肪细胞。研究表明，脂肪组织主要有两种增生方式[8-9]：一是脂肪细胞数目的增加，二是脂肪细胞体积的增大，即脂肪细胞的肥大。一般来说，在个体幼年时期脂肪组织的增生主要是以细胞数量的增加为主，性成熟后，脂肪沉积则主要表现为脂肪细胞的增大，且脂肪细胞的体积越大，脂肪沉积能力越强[10]。
1.2 脂肪沉积过程关键调控因子脂肪沉积是一个受多种转录因子及其网络调控的复杂过程。目前研究得比较透彻的起关键作用的转录因子有过氧化物酶体增殖激活受体-γ (Peroxisome proliferator-activated receptor gamma，PPAR-γ)[11]和CCAAT增强子结合蛋白家族(CCAAT enhancer binding protein family，CEBPs)[12]。
PPARγ是在白色脂肪和棕色脂肪中高表达的动物脂肪沉积关键转录调控因子，能够直接或间接地调控脂肪细胞分化和脂类代谢，它是整个脂肪代谢调控网络的核心，大多数转录调控因子都必须在它介导下才能发挥调控脂肪细胞分化的功能[13]。科学家通过基因敲除实验发现PPARγ基因敲除小鼠脂肪沉积相关转录因子的表达量明显降低，且其胚胎干细胞(Embryonic stem cell，ES)并不能分化出脂肪组织，又经过体外实验发现ES细胞分化为脂肪细胞的程度取决于PPAR-γ基因剂量，实验表明，PPAR-γ对脂肪细胞的体外分化和体内分化都是必不可少的[13]。
CEBPs家族有α、β和δ三个成员，3个成员分别在不同时间参与脂肪分化调控，研究表明，PPAR-γ和CEBP-α上都有CEBPs的结合位点，脂肪细胞分化早期CEBP-β和CEBP-δ大量表达，CEBP-β和CEBP-δ会通过结合位点激发PPAR-γ和CEBP-α的表达，进而启动分化过程[14]。Wu等[15]通过基因转导实验发现，CEBP-α缺失的脂肪细胞积聚的脂滴少，并且无法诱导内源性PPAR-γ表达，这些细胞还完全不存在胰岛素刺激的葡萄糖转运过程，这些结果表明CEBP-α在脂肪形成中发挥重要作用，并表明PPAR-γ和CEBP-α之间的交叉调控是脂肪细胞分化调控的关键组成部分。
近年来，大量的研究不断表明miRNA和lncRNA也可以调控上述这两种脂肪沉积关键基因的表达，对脂肪细胞的分化过程以及脂肪组织的生长发育过程发挥重要作用。
2 miRNA与脂肪沉积 2.1 miRNA概述miRNA是一类长度介于18–25个寡核苷酸的内源性非编码单链核糖核酸分子[16]。它的来源可简述为：细胞核中的RNA聚合酶Ⅱ (RNA polymerase Ⅱ，RNAP Ⅱ)转录基因组中编码miRNA的DNA产生长度可达1 000 nt的初级miRNA (Primary miRNA，pri-miRNA)，pri-miRNA再经由RNA酶Drosha及其伴侣分子DGCR8 (DiGeorge syndrome critical region gene 8，DGCR8)结合形成的微处理器复合物切割形成长达70–100 nt的前体miRNA (Precursor miRNA，pre-miRNA)，pre-miRNA通过转运分子Exportin 5通过核孔运至细胞质中，并经另一种RNA酶Dicer切割形成18–25 nt的双链miRNA，双链miRNA随后结合到AGO蛋白(Argonaute)上形成一个沉默复合物前体(Pri-miRISC)，miRNA的过客链(Passenger strand)被降解，剩下的成熟导向链(Guide strand)与AGO蛋白相互作用形成RNA诱导的沉默复合物(RNA-induced silencing complex，RISC)。其具体形成过程见图 1[17]。
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| 图 1 miRNA的形成过程 Fig. 1 The formation process of miRNA. |
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miRNA不编码蛋白质，它的经典调控机制是通过碱基互补配对的方式以其种子序列(一般是5′端的前8个核苷酸序列)特异性结合靶基因mRNA的3′-非编码区域(3′-Untranslated region，3′-UTR)或5′-非编码区域(5′-Untranslated region，5′-UTR)的特异序列，并通过RISC的方式，实现转录后水平调控靶基因的表达。根据miRNA与靶基因mRNA的3′-UTR或5′-UTR序列互补程度的不同，其调控方式有两种[18]：若完全互补，miRNA可导致靶mRNA的降解；若不完全互补，则阻遏mRNA的翻译，从而抑制蛋白质的合成，两种形式都可达到调控基因的目的。此外，在2017年有研究表明，miRNA除了上述利用种子序列发挥转录后经典调控作用外，还可以通过其非种子序列与靶基因的3′-UTR结合，这就是miRNA基于转录水平的非经典调控作用[19]。
2.2 miRNA在脂肪沉积中的研究近年来，研究人员运用高通量测序技术不断挖掘在动物脂肪组织中发挥作用的miRNA并探究其功能，现已有大量关于miRNA影响动物脂肪沉积的报道。比如，Liang等[20]以中国本土猪和约克夏猪为模型，发现在脂肪组织中的6种miRNA和肌肉组织中的4种miRNA都与脂肪含量等性状密切相关。在肌内前脂肪细胞中，过表达miR-17-5p可抑制核受体共激活因子3 (Nuclear receptor co-activator 3，NCOA-3)、脂肪酸结合蛋白4 (Fatty acid binding protein 4，FABP-4)和PPAR-γ的表达，抑制前体脂肪细胞的分化[21]。在猪皮下脂肪中miR-27的表达与成脂相关基因PPAR-γ和FABP-4的表达呈显著负相关，这表明miR-27可抑制脂肪沉积[22]。也有研究发现，miR-34a可以靶向猪脂联素受体2基因(AdipoR-2)并通过AMPK信号途径来抑制PPAR-α信号传导途径，从而增加肝脏中甘油三脂的含量[23]。Lu等[24]发现miR-212通过靶向沉默信号调节子2 (Silent information regulator 2，SIRT-2)基因并抑制其表达，从而调节脂肪酸合成酶(Fatty acid synthetase，FASN)和甾醇调节元件结合因子1 (Sterol regulatory element binding factor 1，SREBP-1)的表达，最终促进乳腺上皮细胞的脂肪沉积。Liu等[25]探究miR-130b-5p在非酒精性脂肪肝(Nonalcoholic fatty liver disease，NAFLD)发病过程中的潜在作用时发现，下调miR-130b-5p可激活依赖胰岛素样生长因子结合蛋白2 (Insulin like growth factor binding protein 2，IGFBP-2)的AKT途径，从而抑制NAFLD的肝脂质积聚和胰岛素抵抗，提示下调miR-130b-5p可能作为防治NAFLD的治疗手段。Sui等[26]发现miR-142-5P可靶定cateninβ-1 (CTNB-1)，抑制CTNB-1的表达，促进乳脂代谢。
笔者实验室也在该方面取得一定的成果：我们发现在猪肌内前脂肪细胞中，miR-34a和FoxO-1 (胰腺β细胞团的关键调控因子)能调节血小板源生长因子受体α (Platelet-derived growth factor receptor alpha，PDGFRα)的表达，并通过Erk信号通路，促进肌内脂肪沉积[27]。而过表达miR-125a-5p可抑制猪肌内前脂肪细胞的分化，降低总饱和脂肪酸(Saturated fatty acids，SFA)含量和单不饱和脂肪酸(Monounsaturated fatty acids，MUFA)/SFA比值，表明miR-34a和miR-125a-5p可能是一种新型的猪肌内脂肪调控因子[28]。陈粉粉[29]研究发现过表达miR-34c抑制肌内脂肪细胞的增殖，抑制猪脂肪沉积，这表明miR-34c对脂肪沉积具有负调控作用。Shi等[30]发现在猪前体脂肪细胞中的过表达miR-199a-5p会促进细胞的增殖，同时抑制细胞的脂质沉积，通过靶基因预测和实验验证，他们证明窖蛋白1 (Caveolin-1，Cav-1)可能是猪脂肪细胞miR- 199a-5p的靶点，miR-199a-5p可下调Cav-1以促进猪前脂肪细胞增殖、抑制其分化。总之，越来越多miRNA在动物脂肪沉积中的研究不断被挖掘(表 1)。
| MiRNA | Target gene (mRNA) | Function | References |
| miR-130b | PPAR-γ | Inhibits adipogenesis | [31] |
| miR-7134-3p | MARK-4 | Inhibits adipogenesis | [32] |
| miR-103 | PPAR-γ, aP2 | Promotes adipogenesis | [33] |
| miR-429 | PPAR-γ, aP2, FAS | Inhibits adipogenesis | [34] |
| miR-23a | CEBP-α, PPAR-γ | Inhibits adipogenesis | [35] |
| miR-125a | KLF-13 | Inhibits adipogenesis | [36] |
| miRNA-200b | KLF-4 | Inhibits adipogenesis | [37] |
| miR-204-5p | KLF-3 | Promotes adipogenesis | [38] |
| miR-24 | MAPK-7 | Promotes adipogenesis | [39] |
| miR-16-5p | EPT-1 | Promotes adipogenesis | [40] |
| miR-181a-5p | Smad-7, Tcf7l2 | Promotes adipogenesis | [41] |
| miR-149-5p | FGF-21 | Promotes adipogenesis | [42] |
| miR-149-5p | CRTCs | Promotes adipogenesis | [43] |
| miR-99a | NOX-4 | Inhibits adipogenesis | [44] |
| miR-152 | LPL | Promotes adipogenesis | [45] |
| MARK-4: Microtubule affinity regulating kinase 4; aP2: Adipocyte fatty acid binding protein A; FAS: Factor-associated suicide; KLF-3, 4, 13: Kruppel-like factors 3, 4, 13; MAPK-7: Mitogen-activated protein kinase 7; EPT-1: Ethanolamine phosphotransferase 1; Tcf7l2: Transcription factor 7-like 2; FGF-21: Fibroblast growth factor 21; CRTCs: CREB regulated transcription coactivator; NOX-4: NADPH Oxidase 4; LPL: Lipoprotein lipase. | |||
lncRNA是一类由RNAP Ⅱ转录所得的长度在200个核苷酸以上、不能编码蛋白质或只能编码蛋白质微肽的非编码RNA[46]。lncRNA通过类似于编码蛋白质的途径产生，根据其在蛋白编码基因中的位置可以分为5类(图 2)：正义lncRNA (Sense lncRNA)；反义lncRNA (Antisense lncRNA)；双向lncRNA (Bidirectional lncRNA)；内含子lncRNA (Intron transcript lncRNA)；基因间lncRNA (Intergenic lncRNA)。
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| 图 2 lncRNA的分类 Fig. 2 Classification of lncRNA. |
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此外，lncRNA种类繁多、功能复杂，广泛分布于细胞核或细胞质中，相比于miRNA来说，lncRNA在不同物种之间、个体发育的不同阶段都具有表达特异性[47]。现有的研究已表明，lncRNA可以通过参与基因印记、染色体修饰、转录干扰和mRNA降解等过程在表观遗传、转录水平和转录后水平调控基因表达[48]。
3.2 lncRNA在脂肪沉积中的研究lncRNA主要是通过与RNA、DNA或转录因子结合在调节动物脂肪沉积过程中发挥重要作用。比如，研究者发现在莱芜猪和长白猪背最长肌的肌内脂肪中有55个差异表达的lncRNA，其中XLOC_046142、XLOC_004398和XLOC_015408可能分别通过靶向MAP激酶活化蛋白激酶2 (MAP kinase-activated protein kinase 2，MAPKAPK-2)、核受体亚家族1D组成员2 (Nuclear Receptor Subfamily 1，NR1D-2)和醛酮还原酶家族1成员C4 (Aldo-keto reductase family 1 member 4，AKR1C-4)在猪肌内脂肪形成和脂肪沉积过程中起关键调节作用，导致两个猪品种之间存在脂肪沉积差异[49]。Zhang等[50]使用RNA测序分析鸡腹部前脂肪细胞在分化的不同阶段脂肪细胞中的lncRNA和mRNA表达差异，发现差异表达的基因可作用于邻近的编码基因参与和脂肪细胞分化有关的多种途径。Miao等[51]研究金华猪和长白猪肌内脂肪的lncRNA表达谱发现有119个lncRNA差异表达，他们将这些差异表达的lncRNA与mRNA进行了比较，发现其中6种共表达的lncRNA与脂肪沉积和脂质代谢相关的途径有关，这揭示lncRNA对猪肌内脂肪组织中脂肪代谢有调控作用。Wang等[52]发现lncRNA H19通过促进肝细胞MLX互作蛋白(MLX interacting protein like, MLXIPL)表达，激活雷帕霉素靶蛋白复合物1(Mammalian target of rapamycin complex-1，mTORC1)网络诱导肝脂肪变性，结果表明H19可能在调节肝脏脂质代谢中发挥重要作用，并可能成为NAFLD的潜在治疗靶点。
此外，笔者实验室曾通过RNA序列测定发现在八眉猪和长白猪的肌内前体脂肪细胞分化过程中有324个lncRNA时间差异性表达，进一步筛选出了显著上调的lnc_000414深入研究，证明它能通过调节细胞周期相关因子的表达来抑制猪肌内脂肪细胞增殖[53]。同时Wei等[54]发现在关中黑猪的前体脂肪细胞中，PU.1 AS lncRNA作为PU.1 mRNA的反义lncRNA，两者可结合形成二聚体结构，从而阻止PU.1 mRNA翻译，使PU.1蛋白的表达量降低，进而抑制前体脂肪细胞的分化。而AdipoQ AS lncRNA可与AdipoQ mRNA结合形成AdipoQ AS lncRNA/AdipoQ mRNA复合物抑制AdipoQ mRNA的翻译，从而抑制脂肪的发生[55]。Cai等[56]发现敲除lnc-ORA基因后，细胞周期标记物的mRNA和蛋白表达水平降低，证实lnc-ORA可抑制前体脂肪细胞的增殖，同时还发现，敲除lnc-ORA基因也能通过调节PI3K/AKT/ mTOR信号通路抑制脂肪细胞的分化。
3.3 lncRNA与miRNA互作在脂肪沉积中的作用有的lncRNA可以作为miRNA的“海绵”，它可以通过“吸附”miRNA来减少miRNA与mRNA的结合，从而影响mRNA的丰度，这类lncRNA就是竞争性内源RNA (Competing endogenous RNA，ceRNA)。
有研究者在探究长白猪和大白猪肥育性能差异时发现lncRNA TCONS_00010987在大白猪背部脂肪中的表达水平显著高于长白猪，进一步研究发现TCONS_00010987可结合miR-323，从而减少结合瘦素受体(Leptin receptor，LEPR) mRNA的miR-323的数量，使得LEPR大量表达，研究表明TCONS_00010987-miR-323-LEPR调节通路造成长白猪和大白猪肥育性能差异的原因之一[57]。Liu等[58]在研究lncRNA ENST00000608794在地塞米松诱导脂肪变性中的作用时，发现ENST00000608794可作为ceRNA“吸附”miR- 15b-5p，下调miR-15b-5p的表达水平，从而减弱miR-15b-5p对丙酮酸脱氢酶激酶同工酶4 (Pyruvate dehydrogenase kinase isoenzyme 4, PDK-4)的负调控，进而导致脂肪变性。Guo等[59]发现uc.372 (Ultraconserved RNA，一种lncRNA)可以抑制pri-miR-195和pri-miR-4668的成熟，从而减少miR-195/miR-4668的丰度，进而干扰miR-195/miR-4668参与调控脂肪合成和摄取相关基因的表达，最终促进肝脏脂肪变性。Chen等[60]发现lncRNA NEAT 1通过miR-146a-5p靶向RHO相关卷曲螺旋形成蛋白激酶1 mRNA (RHO associated coiled coil containing protein kinase 1，ROCK-1)，并进一步影响AMPK/SREBP通路促进脂肪沉积。Zhang等[61]发现uc.333与miR-223结合可以改善胰岛素抵抗，提示uc.333可能是治疗和预防胰岛素抵抗的有用靶点。诸如此类的有关lncRNA在动物脂肪沉积中的研究还有很多(表 2)。
| LncRNA | Interacting gene(mRNA) | Function | References |
| lncRNA U90926 | PPAR-γ, FABP-4, CEBP-α, AdipoQ | Inhibits adipogenesis | [62] |
| lncRNA HOXA11-AS1 | CEBP-α, DGAT-2 CIDEC, perilipin | Promotes adipogenesis | [63] |
| lncRNA ADNCR | miR-204 | Inhibits adipogenesis | [64] |
| lincRNA-ADAL | hnRNPU, IGF2BP2 | Promotes adipogenesis | [65] |
| lncRNA-OAD | β-catenin | Promotes adipogenesis | [66] |
| lncRNA TINCR | miR-31-5p | Promotes adipogenesis | [67] |
| lncRNA GAS5 | miR-18a | Promotes adipogenesis | [68] |
| lncRNA Gm 12664-001 | miR-295-5p CAV-1 | Inhibits adipogenesis | [69] |
| lncRNA Gm15622 | miR-742-3p SREBP-1c | Promotes adipogenesis | [70] |
| lncRNA PVT1 | PPAR-γ, CEBP-α, aP2 | Promotes adipogenesis | [71] |
| lncRNA KCNQ1OT1 | miR-138 PPAR-γ, RUNX-2 | Promotes adipogenesis | [72] |
| lncRNA Plnc1 | PPAR-γ | Promotes adipogenesis | [73] |
| TCONS 00041960 | miR-204-5p miR-125a-3p | Inhibits adipogenesis | [74] |
| lncRNA Gm15290 | miR-27b, PPAR-γ | Promotes adipogenesis | [75] |
| DGAT-2: The enzyme diacylglycerol acyltransferase 2; CIDEC: Cell death inducing DFFA like effector C; hnRNPU: Heterogeneous nuclear ribonucleoprotein U; IGF2BP2: Insulin-like growth factor 2 mRNA-binding protein 2; SREBP-1c: Sterol regulatory element binding factor 1c; RUNX-2: Runt-related transcription factor 2. | |||
脂肪组织作为一个重要的储能器官，参与调节机体的能量代谢以及一系列生理活动。脂肪沉积是一个复杂的过程，涉及脂肪细胞的增殖和分化、发生和凋亡、甘油三酯的合成和水解等生化过程，这些过程受众多分子和通路的调节，加之各种生物大分子之间存在互作关系，譬如RNA-RNA、DNA-蛋白质、RNA-蛋白质和蛋白质-蛋白质等，因此关于脂肪沉积相关机制的探索任重而道远。近年来虽已发现许多lncRNA和miRNA参与调控动物脂肪细胞的成脂分化过程，但是其作用机制仍需进一步研究和完善，还需要继续挖掘细化已知的调控通路，并积极寻找新的信号通路及重要调控基因，并探索这些已知的通路和基因在脂肪生成中的相互作用等。
随着高通量分子检测手段的出现以及生物信息学分析方法的发展，未来的研究将继续深入探究非编码RNA作为一种生物标记，因lncRNA具有时空表达特异性，所以从脂肪细胞的不同生长阶段筛选与鉴定代表性的特异性lncRNA具有重要意义。科学家已经发现lncBATE10在白色脂肪褐变过程中表达量显著升高，进一步研究表明lncBATE10是诱导体内白色脂肪褐变所必需的调节因子，这项研究为进一步探索白色脂肪褐变的上下游机制奠定了基础[76]。还有研究发现lncRNA CAAlnc1在癌性恶病质小鼠中高表达，并通过抑制脂肪分化参与癌性恶病质脂肪丢失，该研究为癌性恶病质脂肪丢失的治疗提供了潜在的靶点[77]。相信在不久之后，以lncRNA为切入点研究动物脂肪沉积的研究成果会不断涌出，为脂肪代谢紊乱疾病的治疗以及家畜肉品质改善提供新的理论和靶点。
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