妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy，ICP)是妊娠中晚期发生的一种以瘙痒、血清转氨酶升高和血清胆汁酸升高为特征的妊娠期特有疾病。分娩后相关症状及生化异常迅速消失，但也可能在随后的妊娠中复发。ICP的发病率在全世界范围内变化在0.2%～25%之间，中国长江流域ICP发病率为1.0%～4.0%，成都为5.2%，为亚洲高发地区[1]。ICP的病因是多因素的，其易感性受环境、内分泌和遗传因素的影响。有越来越多的数据表明正常妊娠其实也存在轻度胆汁淤积的情况[2]。所以，在妊娠期相关肝代谢通路的正常改变下，其不能维持胆汁酸稳态的妇女可能会发生ICP。另外，有研究表明胆汁酸、胆固醇和葡萄糖的同源性存在联系[3-4]。并有学者发现，ICP患者存在一定的糖耐量受损以及血脂异常[5-6]。
在体内的骨骼肌等细胞表达的过氧化物酶体增殖活化受体γ共激活因子α(peroxisome proliferator-activated receptor-γ co-activator 1α，PGC-1α)的影响下,诱导一种糖基化的Ⅰ型膜蛋白——纤维连接蛋白Ⅲ型结构域蛋白5(fibronectin type Ⅲ domain-containing protein 5，FNDC5)的表达[7]。鸢尾素是由蛋白水解酶剪切 FNDC5 氨基端信号肽及羧基端疏水结构域而形成的含有112个氨基酸的多肽，其相对分子质量约为12kDa[8]。人鸢尾素的氨基酸序列与小鼠几乎完全相同[9-10]。鸢尾素被证实是一种在种属间高度保守并受运动影响的肽类激素[11]。鸢尾素主要由骨骼肌细胞、白色脂肪细胞和小脑中的蒲根野细胞等分泌[10,12]。Huh等[13]研究发现胎盘组织中，鸢尾素mRNA的表达水平较人肌肉组织低，其中鸢尾素蛋白约占胎盘总蛋白的0.0053%。鸢尾素能够促进白色脂肪组织转化为棕色脂肪组织，刺激解偶联蛋白-1(uncoupling protein-1，UCP-1)在白色脂肪细胞中的表达，通过产热及代谢的影响，增加能量的消耗，改善糖、脂代谢[8,14]。在目前国内外鸢尾素相关的众多研究中，大多将其能量消耗和代谢特性作为研究重点，其目的在于探寻代谢紊乱疾病如肥胖、Ⅱ型糖尿病等的治疗新思路。随着深入研究，鸢尾素的下游信号分子包括活性氧(reactive oxygen specices，ROS)、钙离子(Ca2+)、PI3K、p38MAPK、AMPK、ERK、STAT3、Akt等[15]被逐一发现。近些年，鸢尾素的抗炎、抗凋亡和抗氧化应激作用同样受到了学者们的广泛关注，因为这些病理过程常常与疾病例如心肌梗死、肾脏疾病、癌症、肺损伤、炎症性肠病、动脉粥样硬化、肝脏疾病、肥胖和Ⅱ型糖尿病等的发生、进展相关。鉴于鸢尾素的潜在作用，这些相关疾病都可能作为鸢尾素作用及治疗的靶点[16]。
Garces等[17]研究发现在早、中、晚孕期的孕妇胎盘中，蜕膜、细胞滋养层和合体滋养层细胞中有FNDC5的免疫染色。研究中还发现在正常妊娠期间血清鸢尾素水平较未孕女性升高，认为这可能是由胰岛素抵抗引起的一种补偿性反应，降低了褐变和发热量，降低了脂肪的积累，从而对缓解正常孕妇胰岛素抵抗增加有一定促进作用。一项关于在糖尿病患者血清中鸢尾素水平的Meta分析中[18]， GDM患者循环鸢尾素含量明显低于非糖尿病孕妇。Yuksel等[19]进行的病例对照研究发现GDM患者和健康孕妇脐带血鸢尾素之间浓度的差异无统计学意义，GDM孕妇血清鸢尾素水平较正常对照组低，并认为这可能是由GDM患者肌肉中PGC-1α的表达或者功能受损所致。Garces等[17]发现，与正常妊娠晚期的孕妇相比，子痫前期(preeclampsia)患者的血清鸢尾素水平下降，推测可能是由于先兆子痫患者胎盘组织和其他鸢尾素分泌组织的分泌减少所致。一项关于ICP患者血清鸢尾素水平的研究发现，ICP患者血清鸢尾素水平显著高于对照组健康的孕妇。推测鸢尾素的升高是改善ICP代谢紊乱的一种自适应或代偿反应[20]。但该研究也存在样本量不足等问题。
鸢尾素由Bostrom等[8]首先发现后，学者们不断证实鸢尾素能够调节血糖和血脂水平，从而改善胰岛素敏感性。而且还证实鸢尾素在减轻机体氧化应激、炎症反应方面也有相应的保护作用。
1.糖代谢方面
2014年Yuksel等[19]发现GDM患者血清鸢尾素水平明显低于非糖尿病组。推测血清鸢尾素水平可作为前瞻性的新型标志物预示GDM。2016年的一项Meta分析报告显示，在Ⅱ型糖尿病和GDM患者中发现循环鸢尾素水平明显降低，而在Ⅰ型糖尿病患者的鸢尾素水平较高[18]。孕期的血清鸢尾素水平与空腹血糖独立相关[21]。在糖尿病小鼠骨骼肌中，鸢尾素通过调节AMPK途径，改善糖耐量减低和增加葡萄糖摄取，并通过PI3K/Akt/FOXO1信号通路降低其肝中葡萄糖-6-磷酸酶和磷酸烯醇丙酮酸羧激酶(phosphoenolpyruvate carboxykinase，PEPCK)的表达[22-23]。在啮齿类动物和人类的研究中发现胆汁酸与Ⅱ型糖尿病的发病有关[24-25]，并且有学者发现患有ICP的妇女患GDM的风险增加[26]。有研究表明，ICP与糖耐量受损和体重增加有关，而这两者都是GDM的特征[27]。并且发现ICP与血脂异常和糖耐量减低有关，提示二者可能是胆汁酸稳态异常的结果[26-28]。ICP与糖和脂代谢相关的变化可能是由于法尼醇X受体(farnesoid X receptor，FXR)和G蛋白偶联受体5(G protein-coupled receptor 5，TGR5)的活性降低所致，二者也参与了糖和脂的代谢[28-29]。其中胆汁酸激活FXR可减弱葡萄糖异生，降低胰岛素调节的葡萄糖转运体GLUT-4的表达，这些稳态途径的抑制可能解释了在ICP中观察到的血糖升高。
2.脂代谢方面
鸢尾素和/或FNDC5的表达通过调节基因的表达(例如编码脂肪、甘油三酯脂肪酶，激素敏感脂肪酶，以及脂肪酸结合蛋白4等蛋白质)促进脂解和细胞内脂代谢、抑制脂质合成[30-32]。经过体外鸢尾素和FNDC 5处理降低了前脂肪细胞的分化，导致脂肪减少[30]。与对照组相比，经过鸢尾素处理的脂肪细胞体积小，积累的脂类少[31]。在肥胖小鼠中FNDC5过表达及鸢尾素灌注可以缓解高脂血症和高胰岛素血症[31]，皮下注射鸢尾素可以通过抑制AMPK-SREBP2途径来抑制肝胆固醇合成，从而降低血浆胆固醇水平[33]。但在人类的研究中，很多是有争议的。在大多数研究中，鸢尾素水平与不利的脂谱之间存在正相关，例如循环鸢尾素与久坐者和代谢综合征患者空腹甘油三酯[34-35]、中国人的总胆固醇、低密度脂蛋白和空腹脂肪酸[36]，以及韩国青少年的总胆固醇、低密度脂蛋白和甘油三酯[37]呈正相关，以及在心血管高危患者中与高密度脂蛋白呈负相关[34,38]。然而，在中欧的普通人群中，循环鸢尾素与有利的脂谱有关[39]。而在其他研究中，健康的年轻人、体重增加的正常人(>30%)和轻度高胆固醇血症的男性中，没有观察到鸢尾素与血脂参数的相关性[40-42]。导致这些差异的原因目前还不清楚。研究人群的差异或测量鸢尾素的ELISA试剂盒的不同可能是其中的原因。胆汁酸(bile acids)是促进肠道吸收脂质以及参与脂质代谢的必需物质[43]。胆汁酸会增加UCP-1所介导的生热作用以及通过由TGR5所介导的增加棕色脂肪组织的能量消耗[43-44]。在白色脂肪组织中，FXR通过激动剂(fexaramine)的刺激从而促进白色脂肪组织向棕色脂肪组织转变[45]。
3.氧化应激方面
研究发现鸢尾素是一种氧化应激标记物和代谢保护激素[14]。鸢尾素通过减少超氧物、过氧化亚硝酸盐、超氧NADPH氧化酶血红素结合亚基(gp91phox)和诱导型一氧化氮合酶(iNOS)的产生，增加包括谷胱甘肽过氧化物酶(GPX-1)、过氧化氢酶(CAT)和超氧化物歧化酶(SOD) 等抗氧化酶的产生，从而减少糖尿病所致的氧化/硝化应激[16]。另一项研究结果表明，鸢尾素通过抑制PKC-β/NADPH氧化酶和NF-κB/iNOS信号通路的激活，减少高糖/高脂所导致的人脐静脉内皮细胞氧化应激[46]。相对应的，在ICP患者的胎盘中有氧化应激反应的增加，其中基因表达研究表明线粒体基因的表达也受到影响[47]。
4.炎症反应方面
有学者发现，鸢尾素对脂肪细胞有直接地抗炎作用，它在肥胖状态下对巨噬细胞的炎性募集和活化起着至关重要的作用。其中，鸢尾素的治疗会呈浓度依赖性地抑制NF-κB、TNF-α和IL-6的表达，而且鸢尾素在培养的脂肪细胞中使MCP-1的表达减少，从而抑制巨噬细胞的迁移[48]。此外，鸢尾素还能诱导脂肪组织中的巨噬细胞从M1型(促炎型)转为M2型(抗炎型)[49]。FNDC5的表达与抗炎因子IL-10呈正相关，与TNF-α呈负相关[12]。而在鸢尾素处理的原代肝细胞中，促炎症介质包括TNF-α、IL-6、磷酸化的NF-κB、磷酸化的p-38、环氧合酶2(COX-2)明显减少[50]。而在ICP患者胎盘组织中IL-2、IL-4、IL-8、IL-10、TNF-α、干扰素-γ基因表达显著高于正常胎盘组织，并且与ICP患者血清胆汁酸水平呈正相关，结果表明了ICP患者血清胆汁酸水平与相应胎盘炎症反应之间存在明显的正相关关系[51]。
综上所述，鸢尾素目前已经成为众多领域中的热点，与诸多疾病有着紧密的联系，很有可能为这类疾病的病因、治疗提供一个全新的思路。目前对ICP病生过程认识的局限性和环境、遗传等所导致的研究对象的异质性，限制了ICP药物治疗的发展，缺乏疗效确切、安全、适合妊娠期使用的治疗药物。近十年的临床和实验研究认为熊去氧胆酸(ursodeoxycholic acid，UDCA)可能是目前最为有效的药物。现目前，除Kirbas A等[20]对ICP患者血清中鸢尾素的含量及相关指标的相关性有过探索，尚未有直接证据证明鸢尾素与妊娠期肝内胆汁淤积症之间的关系。故还需进一步证明鸢尾素在糖、脂、胆汁酸等代谢途径、炎症以及氧化应激途径中与妊娠期肝内胆汁淤积症的关系。通过相关研究，让鸢尾素成为治疗ICP的新药物变成可能，从而为ICP的病因、治疗做出新的探索。
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