谢帝芝,陈芳,张庆昊,陈军亮,董烨玮,王树启,游翠红,聂国兴,李远友
(1.河南师范大学水产学院,河南新乡453007;2.汕头大学海洋生物研究所/广东省海洋生物技术重点实验室,广东汕头515063)
鱼类LC-PUFA合成代谢调控机制研究进展
谢帝芝1,2,陈芳1,2,张庆昊2,陈军亮2,董烨玮2,王树启2,游翠红2,聂国兴1,李远友2
(1.河南师范大学水产学院,河南新乡453007;2.汕头大学海洋生物研究所/广东省海洋生物技术重点实验室,广东汕头515063)
鱼类是人体获取优质蛋白、特别是LC-PUFA的主要食物来源,人类对水产品需求的增加将主要依赖于水产养殖.然而,鱼油资源短缺、价格昂贵严重制约水产养殖业的可持续发展.弄清鱼类LC-PUFA合成代谢的调控机制,有助于解决在水产饲料中利用植物油替代鱼油存在的不良效果问题,降低或摆脱水产养殖对鱼油的依赖.本文主要从转录水平、转录后水平、表观遗传水平等方面,对鱼类LC-PUFA合成代谢调控机制方面的研究进展进行综述,以期为该领域的研究工作者提供参考.
鱼类;LC-PUFA;合成代谢;调控机制;鱼油替代
多不饱和脂肪酸(Polyunsaturated fatty acid,PUFA)一般指碳原子数≥18、双键数≥2的直链脂肪酸;其中,碳原子数≥20、双键数≥3的PUFA称为长链多不饱和脂肪酸(LC-PUFA).具有重要生理功能的LC-PUFA主要指二十碳四烯酸(又称花生四烯酸,ARA)、二十碳五烯酸(EPA)和二十二碳六烯酸(DHA);它们是人和动物体维持正常生长发育及生理功能的必需脂肪酸(EFA),也是细胞膜磷脂的重要成分;由于其在促进人的大脑发育和防止心脑血管疾病等方面具有重要作用,故有“脑黄金”和“心脑金”之称.
鱼类(特别是海水鱼)不仅提供优质的食物蛋白,它更特别的营养价值在于其是人体获取LC-PUFA的主要食物来源.由于过度捕捞和环境破坏等因素,天然渔业资源呈现下降的趋势,人类对水产品需求的不断增加将主要依赖于水产养殖业的发展.目前,全球约45%的水产品来源于水产养殖,而中国的水产养殖产量占世界水产养殖总产量70%,已连续24年居世界首位[1].然而,水产养殖动物、特别是海水鱼类的LC-PUFA合成能力较弱或缺乏,其配合饲料中一般需要添加富含LC-PUFA的鱼油才能满足机体
正常生长发育对EFA的需要.但是,鱼油资源的短缺且价格昂贵严重制约水产养殖业的健康、可持续发展.为降低或摆脱水产养殖对鱼油的依赖,科研工作者正在努力寻求鱼油替代品.其中,资源较丰富、价格较低的植物油是较适宜的鱼油替代品.现有研究表明,在有些养殖鱼类中,其配合饲料中利用植物油替代鱼油虽然对生长性能影响不大,但由于植物油中缺乏LC-PUFA、而鱼体自身的LC-PUFA合成能力较弱,导致养殖产品中的LC-PUFA含量显著下降,影响鱼肉的品质[2-4].因此,如何提高养殖鱼类自身的LC-PUFA合成能力是解决饲料中植物油替代鱼油问题的关键,而弄清鱼类LC-PUFA合成代谢的调控机制是研发提高鱼体LC-PUFA合成能力方法的基础.本文拟就鱼类LC-PUFA合成代谢调控机制方面的研究进展进行综述,供相关研究者参考.
同其它脊椎动物一样,鱼类缺乏Δ12及Δ15脂肪酸去饱和酶(Fad),因而不能以油酸(18:1n-9)为底物合成PUFA,必须从食物中获取C18 PUFA(主要是亚油酸18:2n-6和亚麻酸18:3n-3)作为基本营养物质.在多种Fad和碳链延长酶(Elovl)的作用下,C18 PUFA前体可被转化为LC-PUFA(图1).然而,不同鱼类的LC-PUFA合成能力不一样,导致其EFA需求种类不同.一般认为,淡水鱼和鲑鳟鱼类具有将C18 PUHA转化为LC-PUFA的能力,故其EFA为18:2n-6和18:3n-3;而海水鱼类除汕头大学李远友课题组在黄斑蓝子鱼中发现具有LC-PUFA合成能力外[5],大多不具有此种能力或该能力很弱,故其EFA为LC-PUFA.鱼体LC-PUFA生物合成能力的强弱,主要取决于其是否拥有一套完整的LC-PUFA合成关键酶体系[6],LC-PUFA合成途径中的关键酶基因的表达量和酶活性直接影响着鱼体的LC-PUFA合成能力.影响鱼类LC-PUFA合成关键酶基因表达及酶活性的主要因素包括饲料脂肪源及其n-3/n-6 PUFA比例、维生素和矿物质等营养因子,温度、盐度、光周期等环境因子,转录因子、激素与遗传因子等,相关内容详见作者前期的综述[7].
图1 鱼类LC-PUFA合成代谢途径[6,8]
鱼类LC-PUFA生物合成关键酶主要有Δ6 Fad、Δ5 Fad、Δ4 Fad、Elovl5、Elovl4和Elovl2(图1);在某些鱼类还有Δ6/Δ5 Fad,即双功能去饱和酶.从分子角度看,上述关键酶活力低下或其基因的缺失是造成鱼体LC-PUFA生物合成功能较弱、甚至缺失的主要原因[9].为了研究鱼类LC-PUFA合成代谢的调控机制,其关键酶基因的克隆及功能验证是基础工作,相关报道见表1.
2.1 Fads
在哺乳动物中,Fads家族包括fads1、fads2、fads3三种基因.fads1和fads2基因产物分别具有Δ5和Δ6 Fad酶活性,而fads3的表达产物没有活性[10].Monroig等[11]将所能检索到的鱼类Fad基因的氨基酸序列进行系统发育树分析,结果表明鱼类Fad都属于fads2基因.但是,与哺乳动物fads2基因功能专一性不同,鱼类fads2基因具有Δ6、Δ4、Δ5、Δ8 Fad多功能性[12].fads基因的多功能性弥补了某些鱼类Δ5 fad基因缺失给LC-PUFA合成造成的影响.例如,Δ6/Δ5 fad基因先后在斑马鱼(Danio rerio)[13]和墨西哥银汉鱼(Chirostoma estor)[13]等淡水鱼中被克隆.本课题组在黄斑蓝子鱼(Siganus canaliculatus)中克隆到Δ4 fad和Δ6/Δ5 fad基因则分别是脊椎动物和海水鱼中的首次发现[8].此外,黄斑蓝子鱼的Δ6/Δ5 fad基因还具有较高的Δ8 Fad酶活性[11],这可能与海洋环境中Δ8 Fad底物(20:3n3和20:2n-6)较丰富有关.
脊椎动物的DHA生物合成存在两条途径:一种是经典的“Sprecher途径”,即22:5n-3经过一步延长反应生成24:5n-3,再经过Δ6 Fad的去饱和反应及过氧化物酶体β-氧化,最终生成DHA[15];另一种是本课题组在黄斑蓝子鱼中首次发现的“Δ4途径”,22:5n-3只需经过Δ4 Fad的去饱和反应即可直接生成DHA[8].最近,在塞内加尔鳎(Solea senegalensis)[16]、墨西哥银汉鱼[13]、泰国鳢(Channa striata)[17]等鱼体内中也发现Δ4途径的存在.
2.2 Elovl
Elovl催化底物脂肪酸和丙二酰-CoA缩合,是C18以上PUFA合成LC-PUFA的关键酶.在哺乳动物中,延长酶家族存在7个基因,根据它们作用底物的特异性不同,分别命名为Elovl1-Elovl7[18].一般认为,Elovl1、Elovl3、Elovl6、Elovl7参与饱和脂肪酸或单不饱和脂肪酸合成的碳链延长作用,此类Elovl在鱼类中报道甚少.研究较多的是Elovl2、Elovl4、Elovl5等三种参与LC-PUFA合成的延长酶.目前,elovl5基因至少已在17种鱼类中得到克隆,而elovl2和elovl4基因仅在极少数鱼体中发现(见表1).
在LC-PUFA合成过程中,Elovl5偏好C18、C20脂肪酸底物,Elovl2通常以C20、C22脂肪酸为底物.从图1可知,Elovl2催化22:5n-3合成24:5n-3是“Sprecher途径”合成DHA的必经之路.然而,至今为止,尚未从海水鱼体内克隆到elovl2基因,这可能是海水鱼LC-PUFA合成能力低下的原因之一[9].有趣的是,不同于哺乳动物Elovl4只能延长C26 PUFA,鱼类Elovl4可有效地将C20和C22延长到C36超长链多不饱和脂肪酸(VLC-PUFA)[19-21].同Elovl2功能相似,Elovl4也能催化22:5n-3合成24:5n-3,这对
于一些elovl2基因缺失的海水鱼合成DHA极为重要性.
表1 在鱼类中报道的脂酰去饱和酶及碳链延长酶基因
鱼类LC-PUFA合成代谢的调控,其核心是LC-PUFA合成关键酶基因的表达调控问题.大量fads和elovl基因的克隆为研究鱼类LC-PUFA合成代谢调控机制提供了基础和可能.特别是本课题组近年来在黄斑蓝子鱼中首次发现和证明海水鱼具有LC-PUFA合成能力,并在该鱼中克隆到Δ4 fad和Δ6/Δ5 fad及elovl4和elovl5基因,从而使其成为LC-PUFA合成途径中所有关键酶基因被阐明的唯一海水鱼类,为我们研究鱼类LCPUFA合成代谢的调控机制、探讨海水鱼LC-PUFA合成能力低下的原因等提供了较理想的模式鱼类.基因表达调控可发生在染色质水平、转录水平、转录后水平、翻译水平以及翻译后水平.目前,有关鱼类LC-PUFA合成代谢的调控机制研究还主要集中在转录水平方面.
3.1 转录水平调控研究
基因转录水平的调控是由启动子和与之相互作用的转录因子共同完成的.启动子中顺式作用元件(cis-acting element)是转录因子的结合位点,通过与转录因子结合调控基因转录的精确起始和转录效率.研究报道,鱼类LC-PUFA合成关键酶基因的表达受其上游启动子中顺式作用元件及转录因子调控[45-47].
3.1.1 鱼类LC-PUFA合成代谢关键酶启动子研究
启动子是基因转录调控至关重要的区域,可结合各种转录因子并对基因转录进行调控.至今为止,鱼类LC-PUFA合成关键酶启动子研究仅在Fads中有报道.Zheng等[45]对大西洋鲑鱼和大西洋鳕鱼的Δ6 Fad启动子进行了分析,结果发现大西洋鲑鱼和大西洋鳕鱼的Δ6 Fad核心启动子区分别位于起始密码子到第一个外显子上游的546 bp和807 bp.本课题组在黄斑蓝子鱼的研究发现,Δ6/Δ5 Fad和Δ4 Fad的核心启动子区则大致在-456~+629 bp和-266~+692 bp[47].Geay等[46]将NCBI中欧洲鲈鱼Δ6 Fad 8条cDNA序列与其基因全长进行比对,发现Δ6Fad中存在两个转录起始位点(TSS1和TSS2).以TSS1为研究对象,结果表明欧洲鲈鱼Δ6 Fad启动子的核心区域大致在-200~+320 bp之间.
对已报道的鱼类Fad启动子序列进行比对分析,发现“NF-Y”、“SRE”元件在不同鱼类fad基因间相当保守;不仅如此,NF-Y和SRE元件的相对位置也十分保守(图2).相同的是,NF-Y和SRE元件的相对位置在两栖类和哺乳类fad基因也十分保守,这可能是进化中存在的保守调控机制[45].在哺乳动物中的相关研究表明,转录因子SREBP1c与SRE元件的结合通常需要邻近区域存在NF-Y或Sp1位点[48].除了上述保守序列外,SRE下游还有一个非常保守的区域(如图2),根据TRANSFAC网站的预测,该保守区可能是PPAR γ-RXRα二聚体的结合位点,其具体功能有待进一步分析.然而,另一保守元件—Sp1仅在大西洋鲑Δ6 Fad和黄斑蓝子鱼的Δ6/Δ5 Fad启动子中存在.比较研究发现,含有Sp1组件的启动子的活性显著高于无Sp1组件的启动子[45,47].在哺乳动物中,Sp1及其相关蛋白可以特异性启动RNA聚合酶II促进基因的转录[49].因此,Sp1是强启动子活性的标志.
图2 几种鱼类fad启动子的序列比对[47]
3.1.2 转录因子
现有研究表明,可能参与鱼类LC-PUFA合成调控的转录因子主要有过氧化物酶体增殖物激活受体(Peroxisome proliferator-activated receptors,PPARs),固醇调节元件结合蛋白(Sterol regulatory element binding proteins,SREBPs),肝核因子(Hepatocyte nuclear factor,HNF),肝X受体(Liver X receptor,LXR),类视黄醇X受体(Retinoid X receptor,RXR)等,分述如下.
3.1.2.1 PPARs
PPARs是配体激活转录因子核受体超家族的一员,在调控脂代谢、炎症、免疫功能、生长发育等方面有重要作用[50].PPARs存在三种亚型,即PPARα、β和γ[51].近年来,PPARs三种亚型的基因已分别从斑马鱼[52]、日本河豚(Fugu rubripes)[53]、金头鲷[53]、欧鲽(Pleuronectes platessa)[54]、欧洲鲈鱼[55]、棕鳟(Salmo trutta)[56]、大西洋鲑鱼[57,58]、黄斑蓝子鱼[59]等鱼体内成功克隆.
PPARα、β和γ都可被内源性脂肪酸及其衍生物激活,但它们在脂代谢的调控过程中所起的功能并不一致.在团头鲂(Megalobrama amblycephala)体内发现,PPARα和PPARβ通过上调线粒体和过氧化物酶体中的肉毒碱棕榈酰转移酶I(Carnitine palmitoyltransferase I,CPT I)、乙酰辅酶A氧化酶(Acyl-CoA oxidase,ACO)等一些参与脂肪酸β-氧化的基因,以促进脂肪酸的氧化,增加LC-PUFA的需求,从而间接地影响LC-PUFA合成代谢[60].不同的是,PPARγ主要参与脂肪积累和脂肪生成的调控[61]. Vagner等[62]发现饲料n-3 LC-PUFA含量低(0.3%-0.5%EPA+DHA)显著促进欧洲鲈鱼幼鱼ppar α和ppar β基因表达.同时,Δ6 fad mRNA水平也显著提高.本课题组的研究发现,黄斑蓝子鱼在低盐环境条件下的LC-PUFA合成量显著高于高盐条件下,且Δ6/Δ5 fad、Δ4 fad、elovl5、ppar γ等参与LC-PUFA合成的相关基因表达量在低盐组鱼体肝脏中高表达,而ppar α和ppar β低表达[63].Corcoran等[64]采用不同水平PPARα配体—氯贝丁酯处理鲤鱼,结果发现ppar α基因表达量随着氯贝丁酯添加水平的增加而增加.同
时,参与脂肪酸氧化代谢的乙酰辅酶A氧化酶基因的表达量及其酶活性也与降固醇酸水平呈正相关.
上述研究表明,PPARs可以通过调控鱼类脂肪酸代谢相关基因的表达,影响LCPUFA的合成代谢.但是,PPARs具体的调控机制在鱼类中尚未阐明.在哺乳动物的相关研究中报道,PPARs被脂肪酸或脂肪酸衍生物激活后,与类视黄醇X受体(Retinoid X receptor,RXR)组合成异源二聚体.异源二聚体一方面可通过配体结合域响应感应物,另一方面可通过高度保守的DNA结合域与靶基因启动子中过氧化物酶体增殖物应答元件(Peroxisome proliferator response element,PPRE)结合,调控靶基因的表达[65].
3.1.2.2 SREBPs
SREBPs属于“螺旋-环-螺旋-亮氨酸拉链”(bHLH-Zip)转录因子家族.无活性的SREBPs前体结合于内质网膜上,需转移至高尔基体上进行蛋白水解,以释放氨基端的bHLH-zip结构域,然后,进入细胞核与胆固醇调节元件(Sterol Regulatory Element,SRE)结合,激活靶基因的转录(图3)[66,67].SREBPs存在SREBP-1a、SREBP-1c、SREBP-2三种亚型.其中,SREBP-1a、SREBP-1c由SREBP-1基因的不同启动子转录,而SREBP-2由SREBP-2基因编码[68].SREBPs三种亚型所调控的基因类型并不一致,SREBP-2主要参与胆固醇合成调控,SREBP-1调控脂质合成代谢相关基因.其中,SREBP-1c参与脂肪酸合成代谢相关的酶基因的转录[69].
在哺乳动物中,SREBP-1c已被证实参与机体LC-PUFA生物合成的转录调控.例如,Nara等[70]发现人Δ6 Fad启动子-90 bp区域受到SREBP-1c激活,却受到LCPUFA的抑制.在小鼠,SREBP-1c能与Elovl 6、Elovl 5启动子结合[71,72].到目前为止,鱼类中仅在Fad基因启动子中发现SREBP-1c结合位点,大西洋鲑和大西洋鳕鱼Δ6 Fad启动子均存在SREBP-1c的结合位点—SRE,且该位点对Δ6 Fad正常转录表达起重要作用[45].Carmona-Anto觡anzas等[73]将大西洋鲑鱼的Elovl5a、Elovl5b、Δ6 Fad启动子与其SREBP-1 N端结构域nSrebp1,以及SREBP-2 N端结构域nSrebp2共转染FHM细胞,双荧光酶报告实验结果表明,Elovl5a、Elovl5b、Δ6 Fad都受SREBP-1和SREBP-2转录调控.营养调控实验也表明,大西洋鲑鱼、欧洲鲈鱼、黄斑蓝子鱼LC-PUFA合成代谢的关键酶基因表达水平同SREBPs水平成正比[74,75,63].上述研究结果表明,SREBPs在转录水平上调控鱼类LC-PUFA合成代谢(图3).
图3 SREBPs转录调控过程
3.1.2.3 LXRs
LXRs是核受体超家族的一员,参与机体多种生理活动的调节,特别是在交叉调控脂肪酸和固醇代谢方面起关键作用[76].在
哺乳动物体内已发现LXR存在LXRα、LXRβ两个亚型[77],但在鱼类中至今仅发现一种L XR亚型,即在斑马鱼[78]、大西洋鲑鱼和虹鳟[79]、黄斑蓝子鱼[80]、草鱼(Ctenopharyngodon idellus)[81]等鱼类中只发现LXRα基因.Archer等[78]认为鱼类缺失LXRβ基因可能是物种进化的结果.
当动物体内缺乏配体时,LXR/RXR二聚体与共阻抑物(NCoR/SMRT)连接;当LXR/ RXR二聚体与脂肪酸、糖类、羟固醇等配体结合时,共阻抑物则脱离二聚体并与共激活剂结合,LXR/RXR二聚体则从细胞质移位至细胞核中,通过与靶标基因启动子上的LXR响应元件(LXRE)结合,启动基因表达(图4).在哺乳动物中的相关研究表明,LXRs通过影响SREBP-1c的活性间接地调节Fad及Elovl5等LC-PUFA合成代谢关键基因的转录[72].然而,在大西洋鲑鱼体内,LXRs不仅可以通过调控SREBPs的表达间接影响elovl5和Δ6 fad基因的转录,而且还可以直接调控Δ6 fad基因的表达[73].
图4 LXR转录调控过程
3.1.2.4 HNF4α
HNF4α隶属于固醇受体超家族.作为一个功能广泛的转录因子,HNF4α可以与肝脏中12%的基因启动子结合,并参与肝脏脂质代谢和转运过程,维持体内脂质代谢平衡[82].
到目前为止,尚未发现HNF4α直接参与LC-PUFA合成代谢调控的相关报道.但是,大量研究表明,HNF4α可通过与其它转录因子或基因相互作用,间接地参与LCPUFA合成代谢调控.例如,Zhang等[83]采用生物信息学分析,发现人PPARγ2启动子区存在一个高亲和力的HNF4α结合位点,在体和离体实验都证实HNF4α可转录激活PPARγ2启动子.过表达HNF4α基因,同样促进了小鼠的PPARα和脂酰辅酶A硫脂酶(参与超长链直链脂肪酸氧化的关键基因)的表达[84,85].在患糖尿病的小鼠体内发现,SREBPs抑制HNF4α基因的表达[86].
3.1.2.5 RXR
RXR可与9-cis视磺酸、甲状腺激素、维生素D、PPARs、LXR等多种配体结合[87].在脂肪酸代谢调控方面,RXR需要与PPARs和LXR形成异二聚体后,才能参与靶基因的调控.例如,PPARs经过脂肪酸或脂肪酸衍生物的激活后,与RXR形成异源二聚体,共同调控脂代谢相关基因的表达.LXRs被胆固醇中间代谢产物激活后,与RXR结合形成异源二聚物,共同调控脂代谢相关基因表达(图3).目前,有关RXR在鱼类LC-PUFA合成代谢调控中的作用还未见报道.
3.2 转录后水平调控研究
近年来,在生物体内发现一类可在转录后水平参与基因表达调控的非编码微小RNA(microRNA,miRNA,miR).miRNAs广泛存在于真核生物,在个体时序性发育、细胞增殖分化和凋亡、器官发育、脂肪代谢等许多生物学过程中起着重要作用.目前,关于miRNA转录后调控机制有多种,如诱导靶mRNA的降解、阻断翻译起始、P-小体形成和翻译激活等[88-91].
在哺乳类的一些研究证实,多种miRNA参与脂类代谢相关的生物学过程调控.例如,miR-33a/b过表达时,人肝脏细胞甘油三酯含量增加,并积累形成脂滴;相反,抑制miR-33a/b的表达,胞内β氧化加剧[92].在小鼠体内,miR-370可以通过两条途径调控脂类代谢:诱导miR-122表达和直接抑制Cpt1α表达.此外,miR-370还可以抑制Cpt1α表达,降低肝脏中脂肪酸β氧化[93].PPARs是脂肪细胞分化中期最重要的两种转录调控因子,是miR-27a、b的直接作用靶标.人肝脏组织中,过表达miR-27b显著抑制PPARα蛋白水平表达[94].miR-143参与调控小鼠脂肪细胞分化与脂肪积累,在分化的脂肪细胞中miR-143表达升高[95],而抑制miR-143表达,则前脂肪细胞分化受到抑制[96].
miRNA在鱼类脂类代谢中的研究作用刚刚起步.在虹鳟的研究表明,miR-122表达可使肝脏胰岛素通路激活,生脂基因表达增加[97].最近,本课题组利用体内和体外实验证明,miR-17通过调节Δ4 Fad表达参与黄斑蓝子鱼肝脏的LC-PUFA调控,这是miRNA参与脊椎动物LC-PUFA合成调控的首次报道[98].
3.3 表观遗传学调控
表观遗传学是指在基因的DNA序列没有发生改变的情况下,基因功能发生可遗传的变化,并最终导致表型变化.表观遗传学主要包括DNA甲基化作用、组蛋白修饰作用、染色质重塑、遗传印记、X染色体随机失活及长链非编码RNA等.
3.3.1 DNA甲基化
近年来,一些研究陆续发现DNA甲基化也参与机体LC-PUFA合成代谢的调控.例如,老鼠Δ6 fad基因启动子被超甲基化后,其肝组织Δ6 Fad酶活性及其mRNA表达量显著下调[99].同型半胱氨酸可以诱导人血液单核细胞中PPARα、PPARγ的DNA甲基化,抑制ppar α和ppar γ基因表达,从而间接地影响机体LC-PUFA合成代谢[100].在啮齿动物营养调控研究中也发现,营养素通过影响Δ6 fad基因启动子甲基化程度,调控基因转录[101].然而,Geay等[46]研究发现,不管欧洲鲈鱼仔稚鱼所摄食的饵料是否富含LC-PUFA,鱼体Δ6 fad启动子区CpG甲基化程度不受影响,但不同饵料显著影响了Δ6 fad基因表达.不同的结果是,饲料脂肪源显著影响了花鲈(Lateolabrax japonicus)fads2基因表达及其启动子甲基化,fads2基因表达量与其启动子甲基化成负相关[102].DNA甲基化对欧洲鲈鱼和花鲈LC-PUFA合成代谢的影响不一致,这可能与鱼种类或生长阶段有关;在鱼类的相关研究有待于进一步全面、深入开展.
3.3.2 组蛋白修饰
组蛋白修饰可以改变染色质状态,或者与其他调节蛋白结合参与DNA的加工过程.组蛋白与DNA的紧密结合使其翻译后修饰在DNA复制、损伤修复以及基因表达中有着重要的作用.Wang等[103]发现组蛋白甲基转移酶G9a可以通过H3K9me2抑制PPARγ的
表达,从而抑制小鼠脂肪生成.Knutson等[104]特异性敲除新生小鼠肝脏组蛋白去乙酰化酶3(HDAC3)基因,结果发现,PPARγ的表达水平增加,脂质、胆固醇合成相关基因如肝X受体、视黄醇类X受体及乙酰辅酶A羧化酶等的表达水平发生改变.在鱼类,相关研究还未见报道.
当今,鱼油资源供不应求、价格昂贵,这严重制约水产养殖业的健康可持续发展.因此,如何降低或摆脱水产养殖对鱼油的依赖已成为确保水产业可持续发展亟待解决的问题,而阐明鱼类LC-PUFA合成代谢的调控机制则有助于解决此问题.为达到此目的,研究者已从多种鱼类中克隆到参与LC-PUFA合成的关键酶基因,包括Δ6、Δ4、Δ5、Δ6/Δ5 fad及elovl2、elovl4、elovl5等,并着手从转录因子、miRNAs、DNA甲基化等不同水平上开展基因表达调控机制方面的研究.借助现代组学方法对鱼类LC-PUFA合成代谢调控网络和调控机制进行深入研究将是今后的重要发展方向.此外,最近在哺乳动物的研究显示,长链非编码RNA(long non-coding RNAs,lncRNAs)在脂质生成和脂肪细胞分化过程中发挥重要调控作用[105-107],lncRNAs在鱼类脂类代谢、特别是LC-PUFA合成调控中的作用也值得探讨.只有通过系统深入的研究,才能全面深入揭示鱼类LCPUFA合成调控的分子机制,研发出提高鱼体自身LC-PUFA合成能力的方法,最终达到提高配合饲料中植物油替代鱼油的比例,降低饲料成本,摆脱水产养殖对鱼油的依赖,促进水产养殖业的健康可持续发展.
为减少水产养殖对鱼油的依赖,除上述主要研究方向外,如下三方面的研究目前也在开展.(1)有研究者采用转基因技术,将具有LC-PUFA合成能力的藻类关键酶基因转入到油料作物中,以使其植物油中含有较高比例LC-PUFA,克服传统植物油中缺乏LC-PUFA的不足,使这些植物油具有鱼油相同的效果[108,109].(2)采用转基因技术提高鱼体的LC-PUFA合成能力.例如,Kabeya等[110]直接将樱鳟的elovl2基因转入到鮸鱼(Nibea mitsukurii)体内,可提高鱼体的22:5n-3含量.(3)采用遗传选育的方法培育LC-PUFA合成能力强的鱼类品种(系).例如,Le Boucher等[111]发现,利用植物性饲料培育大西洋鲑鱼一代后,鱼体利用植物性饲料的能力显著提高.说明个体差异可有效地用于选育LC-PUFA合成能力强的鱼种.总之,LC-PUFA合成代谢调控机制的阐明,植物基因工程的利用和鱼类良种的选育,有助于研发提高鱼体LC-PUFA合成能力的方法、提高配合饲料中植物油替代鱼油的比例,降低水产养殖业对鱼油的依赖,促进鱼类养殖业的绿色健康发展.
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Advance in the Regulatory M echanism s of LC-PUFA Biosynthetic M etabolism of Teleost
XIE Dizhi1,2,CHEN Fang1,2,ZHANG Qinghao2,CHEN Junliang2,DONG Yewei2,WANG Shuqi2,YOU Cuihong2,NIE Guoxing1,LI Yuanyou2
(1.College of Fisheries,Henan Normal University,Xinxiang 453007,China;2.Marine Biology Institute&Guangdong Provincial Key Laboratory of Marine Biotechnology,Shantou University,Shantou 515063,China)
Fish is the main source of high quality protein,especially of LC-PUFA,for human health.The increasing demand of human for aquatic products will mainly depend on aquaculture.However,the lack of fish oil resource and its high price seriously restrict the sustainable development of aquaculture industry.The illumination of regulatory mechanisms of LC-PUFA biosynthetic metabolism in teleost will be helpful for resolving the negative effects of replacing fish oil with vegetable oil in diets,so as to reduce or get rid of the dependence on fish oil in aquatic feeds.This review summaries the advance in studies on regulatory mechanisms of LC-PUFA biosynthesis in teleost from transcriptional,post-transcriptional and epigenetic level,and wishes to provide a reference for researchers in this field.
Teleost;LC-PUFA;Biosynthesis;Regulatory mechanisms;Fish oil substitution
TN 104.3
A
1001-4217(2015)02-0003-17
2015-04-22
谢帝芝(1986-),男,讲师,研究方向:鱼类营养与饲料学.
李远友(1964-),男,教授、博士生导师.研究方向:鱼类生理及分子营养学.E-mail:yyli@stu.edu.cn
国家自然科学基金重大国际合作研究项目(31110103913)和面上项目(41276179),河南师范大学博士启动基金(qd14180),河南省高等学校重点科研项目(15A240004)