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人类AGP是位于9号染色体长臂上的AGP-A、AGP-B和AGP-B′3个相邻基因簇的产物[7]。AGP-A基因编码血清AGP的主要成分AGP1（占血浆AGP的75%），而其他2个基因则编码AGP2 [8]。AGP1有AGP1*S、AGP1*F1和AGP1*F2三种等位基因，其中，AGP1*S和AGP1*F1在全球人群范围内均有分布，AGP1*F2（由AGP1*S和AGP1*F1演变而来[9]）在欧洲人、北非人和西亚人中很常见。相反，AGP2基因在大多数群体中是单态的。到目前为止，大约30个罕见的变异等位基因已通过电泳技术在相应的位点被区分开。在大鼠中，每个基因组只有一个AGP基因，位于第5染色体上。在小鼠中，AGP的3个主要基因（AGP1、AGP2和AGP3）在4号染色体上排列成一个簇，分别编码AGP1、AGP2和AGP3，这些基因与人类和大鼠的AGP基因结构相同，有6个外显子和5个内含子。一些研究表明，组成型的AGP-1水平远远高于AGP2（5倍），AGP1信使RNA（mRNA）的增加而不是AGP2 mRNA的增加是急性期反应期间小鼠AGP mRNA变化的主要原因[10]。此外，尽管AGP3基因序列与AGP2基因序列非常相似，但存在一定的差异。AGP3在内含子1中缺少86个核苷酸，而AGP2在内含子5中有一个额外的（GT碱基起始）28区。已在哺乳动物中观察到同源AGP基因，包括啮齿动物、猫、狗、猪、猴子和人类。小鼠、大鼠、兔和猪的AGP基因与人AGP的同源性分别为44%、59%、70%和70%[11]。
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AGP蛋白含有遗传多态性[12]。急性期刺激只能诱导AGP-A，因此AGP1是AGP家族中唯一的急性期蛋白。在人类中，AGP1前体是由201个残基组成的单个多肽链[13]。在蛋白质加工过程中，前18个残基的一个N-末端分泌信号肽被裂解，最终得到含有183个氨基酸的单链多肽，其中包括两个2硫键。AGP1和AGP2之间有22个氨基酸的差异。其他氨基酸可以出现在位置32和47上，导致多态性[14]。大鼠AGP蛋白的成熟形式分子量为40～44kDa[15]，是一种187个氨基酸的蛋白质，只有一个二硫键，每个分子含有6个N-键复合型低聚糖[16]。
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AGP是一种高酸性蛋白质，其等电点（pI）很低，在2.8～3.8之间[2]. 这种特性使AGP主要与碱性药物（如利多卡因、普萘洛尔、维拉帕米）结合，但也可与中性亲脂性分子（如类固醇激素）和酸性药物（如苯巴比妥）结合，而白蛋白则主要与酸性药物结合[17-18]。大多数药物以不同程度的亲和力与两种血浆蛋白结合。AGP的广泛和可变的唾液酸化是其低且宽pI的原因，这一特性可以影响药物亲和力，并最终影响药物代谢动力学(PK）[6]。由于大多数疾病状态下AGP水平增加[19]，具有高亲和力的药物可能表现出更高的结合状态，从而改变药物的PK特性，表现为药物的总清除率(CL）和静脉输注稳态分布容积(Vss）降低。AGP的酸性特质与大量唾液酸化的聚糖相关。人类AGP含有5个多肽主链的N-连接聚糖，每个N-连接聚糖可形成多个（2个、3个或4个）分支，这些分支都是唾液酸化的位点[20]。去涎酸可导致pI从4.2增加到4.7[21-22]。去涎酸和升高血浆pH值可降低药物与AGP的结合[23-24]。AGP在血清中去涎酸，无唾液酸AGP的内吞和降解由肝脏无唾液酸糖蛋白受体介导，即所谓的“肝结合蛋白”（HBP）[25]。
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蛋白质通常经历翻译后修饰，影响生理功能和半衰期（t1/2）。糖基化寡糖链（聚糖）是常见的翻译后修饰之一，在真核蛋白质中的发生率约为50%[26]。AGP在不同的物种中有不同数量的N-连接的潜在糖基化位点[27]，糖基化主要有3种变化：分支度、唾液酸化和岩藻糖基化。理论上，这种高度的结构多样性将产生超过105种不同的AGP糖型，每种糖型在每个糖基化位点上都可以进行独特的聚糖组合[2]，但在健康人血浆中仅观察到约12～20种聚糖组合。此外，聚糖链上的终末糖是造成聚糖多样性的主要原因，并且这种微异质性强烈依赖于病理生理条件。例如，在急性期反应的早期阶段，表达二氨基聚糖的糖类显著增加，同时AGP岩藻糖基化程度增加明显[28]；在特应性哮喘患者中，尽管血浆和支气管肺泡灌洗液AGP水平在两组之间相似，但与非哮喘患者相比，聚糖分支的程度发生了变化[27]。AGP的糖基化可能受饮食模式的影响,更高的糖基化与更健康的饮食模式相关。糖基化改变与多种疾病的发生发展有关，特别是癌症和2型糖尿病，研究表明饮食可能通过AGP糖基化改变影响疾病状态[29]。
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AGP主要由肝细胞和实质细胞合成[30]。AGP的肝外产生在40多年前就被描述过。人乳腺上皮细胞、Ⅱ型肺泡上皮细胞、人微血管内皮细胞、人粒细胞、单核细胞系THP-1、单核细胞、巨噬细胞和多形核白细胞已被证明能合成和分泌AGP。然而，在T和B淋巴细胞中未发现AGP[24]。组成型AGP基因在肝外器官如肺、乳腺、肾脏和脂肪组织中均有表达[2]。AGP属于先天免疫关键因素的APP家族一员，具有多样化的生物学活性。AGP活性的调节是复杂的。其中炎症不仅诱导AGP血清浓度的增加，而且诱导其碳水化合物部分质的改变，产生大量的糖型，每一种糖型都可能具有不同的活性[31]。AGP的调控主要包括内源性与外源性两方面的因素。
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炎性细胞因子TNFα、IL-1 、IL-8、IL-11和IL-6，以及C-反应蛋白（CRP）、结合珠蛋白（Hp）、血清淀粉样蛋白A（SAA）和血凝素等其他APP，已被证明可调节AGP表达水平[32-35]。研究发现肝、肠、血管壁、胰腺和肾脏中表达的核胆汁酸受体法尼类X受体（FXR）[36]，可以通过小鼠AGP1启动子上游的FXR反应元件激活小鼠肝脏AGP的表达[37]。小鼠AGP基因的诱导更为复杂，涉及到正、负两种转录因子（C/EBPβ[38] 和因子B [39-40]，两者均为核仁蛋白，包含在启动子180 bp区域中），它们在急性期反应中对AGP基因的转录诱导起协同作用。雌激素可以降低肌肉细胞和肝脏细胞的AGP蛋白表达及其启动子活性，阻断雌激素受体或者抑制p38丝裂原活化蛋白激酶可消除这种作用[41]。胆汁酸超载可以诱导肝细胞因子AGP表达[42]。另外，miR-362-3p被鉴定为AGP1的上游调节性miRNA，并对H/R损伤心肌细胞AGP1的mRNA和蛋白表达水平产生负调控[43]。
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反复服用苯巴比妥和利福平可通过独立于炎症途径的机制提高AGP血清水平[44]。维甲酸通过激活维甲酸受体α和维甲酸X受体α，在转录水平上以剂量依赖的方式增加AGP的表达[45]。铅可诱导AGP基因过度表达，可能与NF-κB途径的激活相关[46]。维生素D可诱导人单核细胞AGP1的表达[47]。大环内酯类抗生素影响着AGP的表达水平。例如，克拉霉素可以剂量依赖性地增加正常和糖尿病大鼠血清中AGP蛋白水平以及肝脏中AGP mRNA的稳态水平[48]；红霉素在体外和体内均以剂量和时间依赖的方式增加AGP蛋白的表达[49]。此外，临床研究发现用异丙肾上腺素、儿茶酚胺、纤溶酶原激活物抑制物1、他汀类药物或β受体阻滞剂治疗2型糖尿病或冠心病患者可以调节AGP水平[50]。
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脂肪组织是一种高度异质性和动态的器官，在调节能量代谢和胰岛素敏感性方面起着重要作用。除了在营养传感和能量储存/耗散方面的经典作用外，脂肪组织还分泌大量生物活性分子(称为脂肪因子)，通过旁分泌和/或内分泌作用参与免疫应答和代谢调节[51]。最近，AGP被鉴定为一种脂肪因子，在中枢通过与瘦素受体结合减少食物摄入，在外周通过抑制NF-κB和丝裂原活化蛋白激酶信号减轻脂肪组织炎症分别发挥作用[52-53]。研究发现AGP增加3T3-L1脂肪细胞的葡萄糖摄取活性，并减轻高血糖诱导的胰岛素抵抗以及TNF-α介导的脂肪细胞脂解，改善了肥胖和糖尿病db/db小鼠的葡萄糖和胰岛素耐受性[52]，表明AGP可以通过整合炎症和代谢信号保护脂肪组织免受过度炎症，从而避免引起脂肪组织的代谢功能障碍。另外的研究也表明AGP抑制脂肪组织中脂肪的生成可能是通过抑制胰岛素介导的葡萄糖氧化实现的[54]。最新的研究又将AGP的代谢功能定义为一种新的胆汁酸调节的肝细胞因子。宋浩利等人研究发现胆汁酸诱导肝脏AGP分泌，阻断脂肪细胞分化。在脂肪细胞分化过程中，AGP抑制C/EBPβ、KLF5、C/EBPα和PPARγ等成脂转录因子的基因表达，拮抗脂肪生成信号[42]。肝源性胆汁酸不仅是乳化膳食脂类的天然表面活性剂，而且是葡萄糖和脂类稳态的重要代谢调节剂[36]，这样的能量代谢调节作用可能是通过刺激AGP分泌产生的。脂肪组织中细胞外基质(ECM)的过量沉积被定义为脂肪组织纤维化，是代谢紊乱如肥胖和2型糖尿病的主要原因。近期王鹏源等人研究发现，AGP可以通过激活AMPK抑制TGF-β1的表达，在脂肪组织中发挥直接的抗纤维化作用[55]。定期规律运动克服肥胖所带来的益处，部分源于运动过程中分泌的一些细胞因子（包括蛋白质、肽、酶和代谢物），增加了白色脂肪组织中棕色脂肪细胞特异性基因的表达而诱导白色脂肪组织的褐变[56]。同时，研究发现适当的运动训练能够升高血浆AGP水平[57-58]，基于AGP与脂肪组织的密切关系，它很有可能在促进运动引起的白色脂肪棕色化中发挥一定的作用。
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拉姆塞等[59]研究发现急性期蛋白AGP可以与骨骼肌相互作用，抑制胰岛素刺激的葡萄糖氧化。另外，研究表明AGP具有抗疲劳作用，通过与细胞膜上CCR5受体结合激活AMPK，从而促进肌肉糖原合成增强肌肉耐力[49, 60]。同时，万静静等[49]发现大环内酯类药物红霉素通过升高AGP的表达增强骨骼肌细胞线粒体呼吸链氧化磷酸化能力，促进ATP生成水平来调节肌肉耐力。AMPK是一种关键的细胞能量传感器，在细胞能量水平降低（AMP:ATP和ADP:ATP比率升高）或某些激素刺激（如脂联素）下被激活[61]。在脂肪组织中，AMPK激活促进脂肪酸氧化，抑制脂质合成[62]。研究已经证明脂肪组织中AGP与AMPK存在相互作用[55]，因此，AGP在脂肪组织能量代谢方面的作用以及AGP如何作用于脂肪细胞的AMPK信号，是值得进一步研究的。
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AGP与糖尿病风险的增加密切相关。研究表明1型糖尿病儿童和青少年的血清和尿AGP水平均显著升高，是糖尿病微血管并发症的一个重要独立因素[63]。ChinaMAP通过全基因组关联分析探索了中国人群中2型糖尿病和肥胖遗传相关因素，发现AGP是2型糖尿病风险高频基因位点，进一步的血糖相关分析发现AGP1与空腹血糖（FBG）升高显著正相关[64]。在健康的年轻成年人中，高水平的体脂百分比与血浆AGP的升高具有相关性[65]，表明肥胖作为糖尿病的独立危险因素可能与AGP的升高有关。同时临床研究表明，AGP可以作为一个有意义的生物标志物，可用于区分患有代谢综合征的超重/肥胖女性和代谢健康的女性，而不依赖于体重、脂肪质量和体力活动/体能[66]。在慢性疲劳综合征患者和啮齿动物疲劳模型中，AGP在血液和肌肉等多种组织中显著升高，表明其作为一种抗疲劳蛋白具有指示性生物标志物的潜能[67]。研究发现代谢综合征患者组血清AGP值(P<0.001)显著高于对照组[68]，血清AGP水平与代谢综合征相关临床危险因素密切相关[69]，这些研究发现为利用AGP诊断青少年代谢综合征，以预防未来并发症提供了可能性。这些进一步验证了AGP在调节代谢稳态的作用，其在代谢相关疾病发生发展中可能发挥着重要作用。
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鉴于蛋白质组学和高分辨率质谱技术的最新进展，AGP定量和/或定性分析在疾病诊断、预后和特征描述方面的应用日益增多，使得AGP有可能成为提高相关疾病治疗成功率的鉴别标准。在此我们主要综述了AGP的结构特征、生化特性以及表达的调控，重点总结了AGP在调节代谢中的最新研究进展，表明它可能是一个与肥胖、代谢综合征等代谢性疾病相关的有前景的因素，为代谢性疾病的诊断、预防与治疗提供了一个新的策略方向。
The research progress on the basic characteristics and metabolic regulation of α1-acid glycoprotein
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摘要: 代谢稳态是机体生存必需的基础性功能。α1-酸性糖蛋白(AGP)是一种急性期蛋白，糖基化程度高达45%，具有高亲和力、低容量的特性。虽然AGP的生物学作用尚不完全清楚，但已经证明它可以调节免疫和代谢，并在携带药物转运，维持毛细血管屏障功能等方面发挥着重要作用。综述AGP的结构特征、生化特性，以及AGP的表达调控和代谢调节作用，提示其可能是代谢通路上的一个潜在关键因子，成为代谢性疾病的一个新的研究方向。Abstract: Metabolic homeostasis is a basic function necessary for the survival of the organism. α1-acid glycoprotein (AGP) is an acute phase protein with a glycosylation degree of up to 45%. It has high affinity and low capacity. Although the biological role of AGP is not fully understood, it has been proven that it can regulate immunity and metabolism, and play an important role in transporting drugs and maintaining capillary barrier function. In this review, the structural characteristics, biochemical characteristics and the regulation of AGP expression were reviewed, with emphasis on the regulatory role of AGP in metabolism, suggesting that AGP may be a potential key factor in metabolic pathways, which provides a new research direction for metabolic diseases.
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