2. 吉林农业大学动物科学技术学院, 长春 130118
2. College of Animal Science and Technology, Jilin Agricultural University, Changchun 130118, China
毛囊(hair follicle，HF)是在胚胎发育过程中通过毛囊上皮细胞与毛乳头细胞(dermal papilla cells，DPCs)之间的互相作用而形成的一种复杂的、可再生的器官[1-4]。毛囊的生长发育有其特殊的规律性，且与机体对营养物质的摄入与吸收消化能力相关，若机体营养不良和新陈代谢异常，可引起发质和发色的改变，严重时导致脱发。所以研究通过营养手段来调节毛囊的生长发育是有重要意义的。维生素A是动物体内必需的脂溶性维生素之一，动物机体不能自主合成维生素A类物质，只能从食物中摄取[5]。随着畜牧业的发展，维生素A的利用及对其功能的开发已逐渐成为行业关注的重点及研究热点。近年来的研究发现，维生素A在毛囊生长发育等方面起到了重要作用[6]。因此，本文简要总结了维生素A对动物毛囊发育的调节及影响机制，以期为进一步深入研究其调节动物毛囊发育的作用机理提供参考。
1 维生素A在体内的吸收及代谢途径当前研究发现，除视力外，维生素A在动物体内发挥生理作用的主要形式为视黄酸(retinoic acid，RA)，特别是全反式视黄酸(all-trans retinoic acid，ATRA)[7-10]。维生素A在体内的吸收代谢可分为3个主要过程：肠道摄入、肝脏储存以及通过淋巴和血液传输到靶组织。小肠是摄取维生素A的主要部位，食入的维生素A与胆汁和脂肪一起经小肠黏膜细胞的刷状缘以扩散方式被小肠细胞吸收[11]，在小肠内通过肠腔和肠细胞表面的1种或多种视黄醇酯水解酶(retinyl ester hydrolases，REHs)的作用，膳食视黄醇酯水解为视黄醇。游离的视黄醇与细胞视黄醇结合蛋白-Ⅱ(cellular retinol binding protein-Ⅱ，CRBP-Ⅱ)结合[12-13]，并通过视黄醇酰基转移酶(lecithin retinol acyltransferase，LRAT)被酯化为视黄醇酯[14]。这种视黄醇酯与其他膳食脂质形成乳糜微粒并分泌到淋巴系统。在将新生乳糜微粒分泌到淋巴系统后，经血液循环转移到肝脏星细胞中存储[15-16]，并且将近80%的膳食维生素A以视黄酯的形式储存在肝脏中[17-18]。当周围组织需要时，在肝脏中的视黄醇与细胞视黄醇结合蛋白-Ⅰ(cellular retinol binding protein-Ⅰ，CRBP-Ⅰ)结合，CRBP-Ⅰ携带视黄醇到新合成的血清视黄醇结合蛋白(retinol binding protein，RBP)[14, 19]。视黄醇-RBP复合物随后被分泌到循环中，以满足组织维生素A的需要。靶组织细胞吸收的视黄醇，首先在视黄醇脱氢酶作用下氧化为视黄醛，然后在视黄醛脱氢酶催化下转化为RA[20]。RA通过与细胞视黄酸结合蛋白-Ⅱ(cellular retinoic acid binding protein，CRABP-Ⅱ)结合转运到细胞核中，而其大多数生物学效应是在细胞核内通过调节基因表达的水平发挥的[21]。RA水平主要受属于转录因子的核受体(nuclear receptor，NR)超家族的视黄酸受体(retinoic acid receptors，RARs)亚家族成员介导，即RARα、RARβ和RARγ[22]。RARs与视黄醇X受体(retinoid X receptor, RXR)亚家族成员形成异源二聚体，并通过特异性的结合靶基因启动子中的视黄酸反应元件(RA response elements，RAREs)调节靶基因表达[23-24]。根据机体的生理状态和靶细胞的类型，RA可以调控超过500个基因的转录[25-26]。类视黄醇信号通路的调控是复杂的，类视黄醇对多种组织的作用呈剂量依赖性的[27]。皮肤中RA水平是可以通过调节细胞维生素A代谢来实现，即以视黄醇酯的形式储存、RA合成和RA降解[28]，并且皮肤中RA的水平随饲喂维生素A的水平提高而升高[29]。维生素A主要通过其活性代谢产物RA发挥调控毛囊发育的能力，并且ATRA在毛囊的生长发育的起到的作用在很多研究中得到了验证[28, 30-32]。
2 维生素A与毛囊发育维生素A及其活性衍生物在毛囊的生长、分化和维持中起着重要作用[33-34]。Bazzano等[35]研究表明，局部应用ATRA可以调控毛囊发育周期。Suo等[36]研究发现，饲喂小鼠维生素A可以激活小鼠毛囊干细胞，诱导毛发生长，从而改善脱发情况。朱晓强[6]通过在獭兔饲粮中添加10 000 IU/kg维生素A的研究发现，在此添加水平下生长獭兔毛皮重量和毛皮面积的生产效率达到最大。Williams等[37]外源给予人毛囊13-顺式视黄酸时发现，当添加浓度为10-10~10-7 mol/L时可促进毛囊生长，其中添加浓度为10-9 mol/L时毛囊生长最佳，而当添加浓度为10-6~10-5 mol/L时表现出了毒作用，抑制了毛囊生长。Duncan等[38]研究表明，维生素A调节头发周期和免疫反应，从而改变斑秃的状态，并且饲喂适量的维生素A可以减少小鼠脱发的现象，并且处于生长期的毛囊的百分比较高剂量组高，表皮增生较高剂量组低。Kwon等[31]研究表明，ATRA与米诺地尔(米诺地尔可以通过多种途径促进毛发生长，延长毛囊的生长期)在体内具有协同作用，可以共同促进毛囊生长。ATRA还可以通过影响干细胞来影响毛发周期[28]。维生素A缺乏也会导致头发稀少[39]。刘楚吟[40]研究表明，怀孕的母鼠缺乏维生素A会影响子代的生长发育，饮食减少，毛发脱落失去光泽，影响枕颈部的发育。缺乏维生素A时，会发生毛囊过度角质化现象[41-42]。Hardy[43]研究发现，与对照组相比，过量维生素A可导致毛囊发育畸形。Okano等[30]研究表明，过量的视黄酸可导致脱发。Crampton[44]发现，水貂饲粮中添加300 000 IU/kg维生素A，水貂会出现生产力下降、皮张质量下降等现象。Everts等[45]研究表明，饲喂过量维生素A可使小鼠处于生长期的毛囊明显减少，逐步进入休止期，并且在瘢痕性脱发的小鼠皮肤中发现维生素A代谢改变，高膳食维生素A可能使疤痕性脱发疾病恶化。Ma等[46]研究发现，10-5 mol/L的ATRA可显著降低山羊DPCs的存活率，降低增殖细胞的比例，并抑制细胞生长因子7(fibroblast growth factor 7，FGF7)的表达。Foitzik等[32]研究发现，添加10-6 mol/L的ATRA组与添加10-8和10-10 mol/L的ATRA组相比，添加10-6 mol/L的ATRA对毛干的生长具有很强的抑制作用。这表明适量的维生素A对毛发生长具有促进作用，但过量或缺乏均会导致毛囊功能障碍，所以如何找到精准的RA水平仍需进一步研究。
3 维生素A影响动物毛囊发育的调节机制 3.1 维生素A通过调控转化生长因子(transforming growth factor-β，TGF-β)及其他信号通路调节毛囊发育毛发的生长涉及到信号因子、基因、细胞间的相互作用以及复杂的蛋白质和激素的相互作用[33]。毛囊的发育及周期性生长受到多种通路的调控。这些信号通路的配体、受体、中间的信号分子、下游的转录因子及其靶基因等的改变都影响动物毛囊发育，导致毛发的生长和毛发品质的改变[47-48]。
近期的主要研究集中在RA通过调控TGF-β信号转导通路影响毛囊发育。TGF-β是一个多功能细胞因子家族，包括3个亚型：TGF-β1、TGF-β2和TGF-β3，可以通过调节细胞的生长、增殖、分化、凋亡等过程在组织与器官的发生和形成等生物过程发挥重要的功能[49]。Li等[50]研究发现，激活TGF-β/Smads通路被报道对毛发生长起抑制作用。TGF-β2是一个多功能的生物调节分子，具有抑制上皮细胞生长、刺激角质形成细胞凋亡的作用[51-52]。TGF-β2在调节毛囊周期上具有两面性，一方面，Foitzik等[53]发现，TGF-β2基因敲除小鼠的毛囊形态发生明显延迟，毛囊数量减少50%，证明在毛囊形态形成过程中TGF-β2起到了积极的作用；Oshimori等[54]发现，TGF-β2在抑制骨形态发生蛋白(BMP)信号和促进毛囊干细胞激活具有显著的影响；另一方面，TGF-β2已被证明在鼠和人毛囊生长中作为有效的毛发生长退行期诱导物，显著抑制毛发角质细胞增殖和诱导凋亡[55-57]。TGF-β2可以通过线粒体途径激活半胱氨酸天冬氨酸蛋白酶(caspase)导致细胞凋亡[58]。Tsuji等[59]在体外培养的人生长期毛囊的培养基中加入20 ng/mL TGF-β2培养2 d后发现，TGF-β2可以激活凋亡因子caspase-3和caspase-9的表达。研究表明，RA在多种细胞如角质细胞、成纤维细胞和胰腺癌细胞上可以诱导TGF-β2的表达[60-61]，并且Namachivayam等[62]发现RA处理后的IEC6细胞TGF-β2 mRNA和蛋白质的表达呈时间和剂量依赖性增加，并提高了TGF-β2启动子的活性。Foitzik等[32]进一步研究证明，外源给予过多RA可通过提高人毛囊毛乳头细胞中TGF-β2的表达而抑制毛囊生长。所以RA对毛囊的影响可能是通过诱导TGF-β2的表达激活caspase-3等凋亡因子，从而诱导毛囊上皮细胞凋亡，致使毛囊从生长期到退行期的转变。
Kwon等[31]研究表明，在体内ATRA与米诺地尔具有协同作用，它们通过激活细胞外信号调节蛋白激酶(ERK)和蛋白激酶B(Akt)信号通路来延长细胞存活时间，并通过增加B细胞淋巴瘤因子-2(Bcl-2)/Bcl-2相关X蛋白(Bax)比率和下调p53和p21基因的表达来预防DPCs和上皮细胞的凋亡。Wnt信号通路可以通过刺激毛囊干细胞分化，促进毛囊从休止期进入到生长期[63]。许多研究表明，在小鼠发育和毛囊再生过程中，RA通路可以抑制Wnt信号通路[64-65]。Collins等[66]研究发现，RA结合蛋白的表达模式既可以通过RA的直接作用于皮肤来调节，也可以通过β-连环蛋白(β-catenin)或Notch通路途径的转录调控来调节。所以，维生素A可以通过影响信号通路影响毛囊发育。我们需要进一步的研究来更好地了解RA在毛囊内的作用机制，为脱发疾病提供更好的治疗。
3.2 维生素A通过影响脂类代谢调节毛囊发育皮脂腺(sebaceous gland，SG)是皮肤的附属结构，大多位于毛囊和立毛肌之间，在毛囊形成过程中由毛囊皮脂腺单位发育而来。SG除了对头发和皮肤起到保护和防水的作用外，对头发纤维鞘的分离和毛囊的完整性同样重要[67]。过氧化物酶体增殖物激活受体-γ(peroxisome proliferators-activated receptors γ，PPARγ)是一种是脂类代谢具有调节作用的脂类激活转录因子，在SG的发生过程中起主要作用[68]。PPARγ刺激角质形成细胞和皮脂细胞分化，以及表皮脂质合成[69]，在启动皮脂腺油脂细胞分化过程中发挥着独特的作用[70]。当脂质代谢途径受到干扰时，会导致严重的毛囊损伤[71]。在PPARγ基因敲除小鼠中发现隆突干细胞中PPARγ的缺失导致小鼠脱发、皮脂腺萎缩[72]。维生素A对脂类代谢相关基因的表达及其信号通路、脂肪细胞的数量、脂肪细胞因子分泌和表观遗传学修饰等方面有调节作用，这些调控作用最终可影响到脂肪代谢[73]。视黄酸可以抑制BMP2诱导的脂肪细胞分化，从而抑制PPARγ表达[74]，并且PPARγ同RXR形成二聚体调控脂类代谢[75]。所以，维生素A也可能是通过调节皮脂腺功能从而影响毛囊的生长。
3.3 维生素A调节毛囊发育相关基因及酶类的表达视黄醇通过与核受体结合发挥作用，核受体又与其他转录因子相互作用，协调基因表达[27]。Duncan等[38]研究发现，与对照组相比，斑秃病变中参与维生素A代谢的基因明显上调，并且这一发现在人、小鼠和大鼠皮肤的免疫组化试验中的得到验证。酰基辅酶A:二酰甘油酰基转移酶1(acyl-CoA: diacylglycerol acyltransferase1，Dgat1)在体外可以催化ATRA反应[76]。在Dgat1基因敲除小鼠(Dgat1-/- mice)皮肤中的RA水平下降并存在周期性脱发的现象，当补充充足的维生素A时，这种状态会缓解，并且ATRA的靶基因CRBP-Ⅰ和CRABP-Ⅱ的表达量明显升高[29]。
维生素A还可通过影响机体的相关酶类分泌影响毛囊发育。RA与细胞视黄酸结合蛋白-Ⅰ(cellular retinoic acid binding protein-Ⅰ，CRABP-Ⅰ)的结合后，CRABP-Ⅰ将细胞质内的RA转移至内质网进而被细胞色素P450氧化酶(cytochrome P450，CYPs)代谢，降解成非活性的4-oxo-RA、4-OH-RA和18-OH-RA[77]，在人表皮中的CYP26A1和CYP26B1的基因表达水平都是通过RA诱导的[78]。目前发现CYP26A1在毛囊、皮脂腺中表达[79]，并且CYP26A1通过反馈抑制回路在维持RA水平方面起到了关键作用[80]。Everts等[45]研究发现，RARβ、CYP26A1在瘢痕性脱发中的表达增高。Okano等[30]发现，若皮肤中缺乏RA降解酶CYP26B1的小鼠出现毛囊发育缺陷，RA水平决定了毛囊的向下生长和弯曲。综上，参与类维生素代谢的基因可以调控毛囊的发育，并且CYPs同毛囊发育密切相关。
4 小结目前，相关文献证实了维生素A在毛囊发生、发育及分化过程的重要作用，并且维生素A可以通过调节信号通路、脂类代谢、相关基因的表达和相关酶的分泌发挥其独特的生理作用。但维生素A缺乏或过量产生的毒性对机体毛囊发育产生不利影响的研究仍然较少。羊、貂、狐、貉和兔的养殖主要或部分以毛皮作为经济产品，因此，更应加大在毛皮动物生产中精准的维生素A需要量的研究。维生素A影响毛囊发育的机制非常复杂，还有待深入挖掘。未来可根据维生素A调控毛囊形态发生过程中重要的信号通路和关键的转录调节因子等方面展开研究，可为维生素A在动物的脱发机制及毛发再生等方面奠定理论基础。
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