引用本文
汤小朋,
刘虎,
杨淑芬,
方热军.
表皮生长因子在动物肠道无机离子及其他营养物质吸收中的作用[J]. 动物营养学报, 2016, 28(8): 2317-2323.
TANG Xiaopeng,
LIU Hu,
YANG Shufen,
FANG Rejun.
Roles of Epidermal Growth Factor on Absorption of Inorganic Ions and other Nutrients in Animal Intestine[J]. Chinese Journal of Animal Nutrition, 2016, 28(8): 2317-2323.
表皮生长因子在动物肠道无机离子及其他营养物质吸收中的作用
1. 湖南农业大学动物科学技术学院, 长沙 410128;
2. 湖南畜禽安全生产协同创新中心, 长沙 410128
2. 湖南畜禽安全生产协同创新中心, 长沙 410128
摘要: 表皮生长因子（epidermal growth factor, EGF）是生长因子家族成员之一，具有促进细胞生长、细胞迁移、细胞增殖、伤口愈合、骨骼愈合以及营养物质转运等生物学功能。大量研究表明EGF对钠离子、氯离子、镁离子、无机磷、葡萄糖、谷氨酰胺、小肽、5-羟色胺等物质的转运具有促进作用。本文旨在概述EGF对营养物质转运的影响，为EGF在动物生产上的应用提供参考。
关键词:
EGF
肠道
无机离子
营养物质
Roles of Epidermal Growth Factor on Absorption of Inorganic Ions and other Nutrients in Animal Intestine
1. College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China;
2. Hunan Co-Innovation Center of Animal Production Safety, Changsha 410128, China
2. Hunan Co-Innovation Center of Animal Production Safety, Changsha 410128, China
Abstract: Epidermal growth factor (EGF) is one of the members of growth factor family, which can promote cell growth, cell migration, cell proliferation, wound healing, bone healing and nutrient transport and so on. EGF is known to positively influence intestinal nutrient transport processes, such as sodium, chloride, magnesium, inorganic phosphate, glucose, glutamine, peptides and serotonin. This review was mainly to outline the effects of EGF on nutrients transport, and to provide a better understanding of the utilization of EGF in animal production.
Key words:
EGF
intestinal
inorganic ion
nutrients
表皮生长因子(epidermal growth factor, EGF)是Stanley Cohen在1962年从小鼠下颌腺中分离提纯出的一种单链多肽类活性物质[1]。EGF是最小的一种多肽，分子质量为6 ku，含有53个氨基酸残基，分子内含有3个二硫键，对热和酸稳定，不易被胰蛋白酶及糜蛋白酶消化，广泛存在于乳液、唾液、尿液、肠液、血液、羊水等液体中[2]。EGF与其受体(EGFR)结合后，激活酪蛋白激酶，从而发挥其生物功能，如促进细胞生长[3]、细胞迁移[4-5]、细胞增殖[5-6]、伤口愈合[7]、骨骼愈合[8]以及营养物质转运[9-11]等。葡萄糖、氨基酸、脂肪酸、维生素、无机盐等营养物质经小肠黏膜由胃肠道腔转运至上皮细胞对动物生长与发育至关重要。研究表明EGF与钠离子(Na+)[10]、镁离子(Mg2+)[12]、无机磷[13-14]、葡萄糖[9, 11]、谷氨酰胺[15]等营养物质的转运有关，对促进动物生长、提高动物生产性能有重要作用。本文旨在概述EGF对动物肠道无机离子、葡萄糖及谷氨酰胺等营养物质吸收的影响，为EGF在动物生产上的应用提供参考。
1 EGF对无机离子吸收的影响 1.1 Na+EGF参与许多上皮细胞离子通道的调节，在离子吸收过程中发挥重要作用[16-20]。Na+对容量调节及维持血压有重要作用，它的吸收受许多转运蛋白的调控，包括电中性的钠氢交换子2、3、8(Na+/H+ exchangers, NHE2、NHE3、NHE8)[21]与带电的Na+通道蛋白(epithelial sodium channel, ENaC)[22]。ENaC主要在肾脏与结肠表达[16, 22]，EGF可刺激ENaC的表达，从而介导Na+在肾脏的重吸收与在结肠的主动转运[16, 22-23]。NHE2主要在肠道顶膜或刷状缘膜表达[24-25]，EGF可刺激大鼠及人NHE2 mRNA表达及提高NHE2活性[25-26]，从而介导Na+由肠道腔转运至上皮细胞，促进Na+的吸收。NHE3主要在回肠顶膜表达，在Na+跨上皮细胞转运中起主要作用[27]。EGF是否通过刺激NHE3的表达而介导Na+转运还未见报道。NHE8主要在肾脏与小肠刷状缘膜表达，NHE8也可促进Na+的吸收，但它主要在动物发育早期NHE2和NHE3缺乏的情况下起作用[28]。Xu等[21]研究发现EGF处理大鼠与人Caco-2细胞NHE8 mRNA表达下降，NHE8蛋白丰度也降低；人Caco-2细胞NHE8基因启动子转染活性同样降低。这可能是因为EGF促进了NHE2的表达[25]，而在NHE2存在的条件下，NHE8不发挥促进Na+吸收的功能[28]。
1.2 氯离子(Cl-)水的肠跨上皮细胞转运是一个重要的过程，它有助于维持机体体液与电解质平衡，维持黏膜表面适宜的水分和作用及增强黏膜屏障功能[17-18]。离子主动转运驱使体液跨膜运动，其中Cl-分泌是体液分泌的主要驱动力。Cl-分泌异常调节可扰乱体液转运，导致传染性疾病、炎症性肠病和囊性纤维化等疾病的发生[29]。研究表明EGF可通过刺激Na+/钾离子(K+)/2Cl转运蛋白(Na+/K+/2Cl- cotransporter, NKCC1)的表达促进Cl-的分泌[17]。Cl-分泌过程所需的能量来自基底侧的Na+/K+-ATP酶泵，从细胞中泵出3Na+替换2K+，形成化学梯度，通过NKCC1转运1Na+、1K+和2Cl-进入细胞[30]。此外，EGF可通过上调钙离子(Ca2+)激活Cl-通道(Ca2+-activated Cl- channel, CaCC)来调节Cl-分泌[18, 31]。膜蛋白16A(transmembrane protein 16A, TMEM16A)可调节CaCC的活性，抑制TMEM16A的表达会导致CaCC活性降低[32]。Mroz等[18]用EGF处理T84结肠上皮细胞发现TMEM16A mRNA及蛋白表达显著提高，CaCC电流增大，而TMEM16A抑制剂(T16Ainh-A01)处理后CaCC电流减弱，说明EGF可通过调节TMEM16A的表达来调节CaCC的活性进而调控Cl-的分泌。
1.3 Mg2+Mg2+是机体含量第四丰富的阳离子，是许多酶的辅因子，与能量代谢、基因转录及蛋白合成等细胞进程有关[33]。因此，血浆与细胞中Mg2+水平的精确调控对维持细胞正常功能至关重要[2]。Mg2+的动态平衡及在细胞内的浓度主要由小肠吸收的Mg2+与肾脏重吸收和分泌的Mg2+共同决定。Mg2+的吸收有2条途径：细胞旁路途径与跨细胞转运途径[33]。研究表明在远端小肠、结肠及肾脏中表达的瞬时感受器电位M6离子通道(transient receptor potential melastatin 6, TRPM6)可介导Mg2+跨细胞转运[2, 33]。目前，大量研究表明EGF可刺激肾脏远曲小管Mg2+通道TRPM6表达，从而促进Mg2+重吸收[34-36]。但EGF是否可通过调节肠道TRPM6的表达而促进Mg2+的吸收还未见报道，EGF能否促进肠道TRPM6的表达有待进一步研究。
1.4 无机磷磷是动物必需的矿物质元素之一，在动物生长发育、骨骼形成、能量代谢、核酸合成、细胞信号转导以及维持血液酸碱平衡中起着重要作用[37-38]。肠道磷吸收受许多因素调控，EGF是调节肠道磷吸收的重要因素之一[13-14]。研究表明小肠跨上皮细胞顶膜磷主动吸收是由Na+依赖Ⅱb型磷转运蛋白(typeⅡb sodium dependent phosphate cotransporters, NaPi-Ⅱb)介导的[39]。因此，可推测能调节NaPi-Ⅱb表达的因素可能与肠道磷吸收有关。Xu等[13]研究发现EGF可在转录水平上调节大鼠小肠细胞及人小肠细胞(Caco-2细胞)NaPi-Ⅱb基因的表达，使NaPi-Ⅱb mRNA丰度下降40%~50%。进一步研究表明EGF通过修饰c-myb蛋白与NaPi-Ⅱb基因的亲和力，然后通过蛋白激酶C/蛋白激酶A(protein kinase C/protein kinase K，PKC/PKA)和丝裂原活化蛋白激酶(mitogen activated protein kinase，MAPK)信号通路实现下游启动子功能的调节，从而抑制NaPi-Ⅱb的转录活性而降低其表达水平[14]。由此说明EGF可通过调节NaPi-Ⅱb的表达来影响肠道磷的吸收。
2 EGF对有机物吸收的影响 2.1 氨基酸及小肽饲料中的蛋白质只有被水解为游离氨基酸或小肽才能被机体吸收利用。谷氨酰胺是血液中含量最丰富的氨基酸，是蛋白质、核酸、葡萄糖、氨基糖等生物合成过程中重要的前体物，也是肠黏膜上皮细胞与淋巴细胞能量的主要来源[40-41]。Na+依赖中性氨基酸转运蛋白(Na+-dependent neutral amino acid transporter, ASCT2)是一种广谱氨基酸转运载体，能转运丙氨酸、丝氨酸、半胱氨酸、天冬酰胺、缬氨酸、蛋氨酸及谷氨酰胺等中性氨基酸[42]。体内外研究表明EGF可通过提高肠道上皮细胞ASCT2 mRNA、蛋白表达量及ASCT2转运活性，促进肠上皮细胞谷氨酰胺的吸收[15, 40, 43]。Ray等[15]研究表明EGF作用人肠道细胞10 min后，细胞对谷氨酰胺的吸收提高50%。Huang等[40]研究发现在人类缺血性损伤肠上皮细胞中ASCT2表达量下降，而经EGF作用后ASCT2表达量迅速恢复。
EGF对小肽吸收的研究较少，零星的报道表明EGF长期(26~28 d)处理人Caco-2细胞会抑制甘氨酸肌氨酸(glycylsarcosine，Gly-Sar)的转运，这种抑制是通过下调小肠Ⅰ型肽转运载体(peptide transporter 1, PepT1)的表达实现的[44]，而EGF短期(5 min)刺激可增加Caco-2细胞吸收Gly-Sar的能力，但并不影响PepT1 mRNA的表达量[45]。这与Xu等[46]在猪上的研究结果相反。Xu等[46]研究表明EGF处理小猪空肠与回肠PepT1 mRNA表达量增加，促进小肽的吸收，从而促进动物的生长。
2.2 葡萄糖葡萄糖是真核细胞主要的碳源和能量来源。葡萄糖转运至哺乳动物细胞是葡萄糖利用的限速步骤。已证实有2种葡萄糖转运蛋白参与葡萄糖转运：一种是高亲和、低转运能力的钠-葡萄糖共转运蛋白1(sodium/glucose cotransporter 1, SGLT1)；一种是低亲和、高转运能力的葡萄糖转运蛋白2(glucose transporter 2, GLUT2)[6, 46]。一般认为肠腔内葡萄糖由位于刷状缘膜SGLT1转运至上皮细胞，再由位于肠道基底膜GLUT2将细胞内的葡萄糖转运至门腔静脉[47-48]。但是，研究发现，在肠腔葡萄糖浓度过高时GLUT2可增加上皮细胞葡萄糖转运[47-49]。
EGF对GLUT2表达的影响研究较少，得到的结果也不尽相同。Bedford等[6]研究表明EGF对断奶仔猪GLUT2 mRNA表达无影响。而Xu等[46]研究表明EGF可促进断奶仔猪空肠与回肠GLUT2 mRNA表达。
SGLT1主要介导跨小肠刷状缘膜葡萄糖转运[6, 11]，SGLT1的上调表达可使葡萄糖吸收量增加，提高能量摄取水平[50]，且SGLT1介导的葡萄糖吸收能抑制微生物作用引起的细胞凋亡及炎症反应[51]，从而影响动物生产性能。Cellini等[52]报道，给雌性家兔子宫内胎儿提供含EGF的羊水，可增加小肠葡萄糖的摄取量。这是因为EGF可刺激肠黏膜细胞刷状上的SGLT1移位到黏膜刷状缘顶端，增加刷状缘上SGLT1浓度，将肠腔内葡萄糖转运至上皮细胞，影响能量摄入[11, 52]。Bedford等[6]及Xu等[46]研究均表明EGF可促进断奶仔猪肠道SGLT1的表达。Wang等[11]利用小鼠及人Caco-2细胞研究了EGF促进肠道葡萄糖吸收的分子机制：EGF在转录水平调控SGLT1基因的表达促进肠道葡萄糖吸收，环磷酸腺苷相应元件结合蛋白(cAMP response element-binding protein, CREB)在EGF诱导的SGLT1基因表达过程中是必要的，其通过EGFR与磷脂酰肌醇-3-羟激酶(phosphatidylinositol 3-hydroxy kinase, PI3K)信号通路激活并磷酸化促进SGLT1基因表达与肠道葡萄糖吸收。其后用小肠发炎小鼠模型研究表明在炎症情况下EGF表达量下降，CREB活性下调，SGLT1表达下降，葡萄糖吸收活性也下降[11]，进一步证实了EGF促进肠道葡萄糖吸收的分子机制。
2.3 5-羟色胺(serotonin，5-HT)5-HT又称血清素，是一种重要的生物胺。内源性5-HT主要来自胃肠道，在肠嗜铬细胞由色氨酸羟化酶合成，调控肠道蠕动与分泌功能[53]。但是，肠黏膜5-HT含量过高会引起肠道炎症及腹泻等肠道疾病的发生[54]。5-HT转运蛋白(serotonin transporter, SERT)主要存在于肠上皮细胞顶膜，可将细胞外5-HT转运至细胞内，通过细胞内的单胺氧化酶等酶类将其钝化，维持肠道5-HT正常水平[55]。EGF可促进肠上皮细胞SERT的表达，促进5-HT的吸收[53, 56]，对调节肠道功能及维持肠道健康等具有重要作用。EGF调节5-HT吸收的可能机制为：EGF通过激活EGFR启动子在转录水平上调节SERT的表达[56]。Cui等[53]研究表明在IEC-6细胞中EGF处理后SERT活性增加，添加EGFR激酶抑制剂后抑制SERT基因表达也证实了EGF通过激活EGFR调控SERT的表达，从而促进5-HT的吸收。
综上，EGF对Na+、Cl-、Mg2+、无机磷、谷氨酰胺、小肽、葡萄糖及5-HT吸收的影响见表 1。EGF可刺激肠道NHE2、NHE8、NKCC1、CaCC、ASCT2、SGLT1及SERT的表达，促进Na+、Cl-、谷氨酰胺、葡萄糖及5-HT的吸收。EGF可调控肠道NaPi-Ⅱb的表达，但是否影响磷的吸收还需进一步研究。EGF是否通过调节肠道TRPM6的表达来调节Mg2+的吸收还未见报道。EGF对小肽吸收的报道不一致，具体通过何种途径调控小肽的吸收还需进一步研究。
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表 1 EGF对无机离子及其他营养物质吸收的影响 Table 1 Effects of EGF on the absorption of inorganic ions and other nutrients |
作为一种重要的生长因子，EGF在促进细胞增殖、细胞分化、细胞生存等方面具有重要作用。大量研究表明EGF对Na+、Cl-、Mg2+、无机磷、葡萄糖、谷氨酰胺、小肽和5-HT等物质的转运具有促进作用。但关于EGF促进营养物质吸收的机制研究还不够深入。因此，进一步阐明EGF促进营养物质吸收的机制可能会成为今后的研究热点，以求为EGF在动物生产上的应用提供科学依据。
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