赵 健 李 伟 姚定康

第二军医大学附属长征医院内科教研室(200003)

·综 述·

法尼醇X受体在原发性胆汁性胆管炎治疗中的作用

赵 健 李 伟 姚定康*

第二军医大学附属长征医院内科教研室(200003)

原发性胆汁性胆管炎(PBC)是一种常见的胆汁淤积性肝病。熊去氧胆酸(UDCA)是目前惟一被批准并能有效治疗PBC的药物，但高达40%的PBC患者对UDCA应答不佳。法尼醇X受体(FXR)具有抑制胆汁酸合成、调控胆汁酸转运和抗肝纤维化的作用。本文就FXR在PBC治疗中的作用作一综述。

原发性胆汁性胆管炎； 法尼醇X受体； 奥贝胆酸； 胆酸； 治疗

原发性胆汁性胆管炎(primary biliary cholangitis, PBC)是一种以肝内小胆管破坏为特征的慢性胆汁淤积性肝病，最终导致肝纤维化并引起多种相关并发症。熊去氧胆酸(UDCA)是目前惟一被批准并能有效治疗PBC的药物，但高达40%的PBC患者对UDCA应答不佳[1]。因此，亟待探寻其他能有效治疗PBC的药物。

法尼醇X受体(farnesoid X receptor, FXR)是第一个被证实为以胆汁酸为天然配体的核受体，具有抑制胆汁酸合成、调控胆汁酸转运和抗肝纤维化的作用。其广泛分布于肝脏、肠道、肾脏等部位，因可被法尼醇及其相关分子激活而得名。随着FXR作用机制的逐步揭示，FXR激动剂的研发在PBC治疗领域备受关注，且已取得一定的研究成果。本文就FXR在PBC治疗中的作用作一综述。

一、FXR的作用

1. 抑制胆汁酸合成：胆汁酸合成过程中需多种酶催化，其中胆固醇7α-羟化酶(CYP7A1)是合成反应中的限速酶，而细胞色素P8B1(CYP8B1)是使鹅去氧胆酸(CDCA)羟基化为胆酸的关键酶。FXR激活后可上调小异二聚体伴侣(small heterodimer partner, SHP)表达，后者可抑制肝X受体(LXR)、肝受体同系物-1(LRH-1)、肝细胞核因子4α(HNF4α)等多种核受体基因转录[2-3]。LRH-1、HNF4α是正向调控CYP7A1、CYP8B1表达的因子[4-5]，因此FXR可通过SHP间接抑制胆汁酸合成限速酶的生成，从而抑制胆汁酸合成。此种调节机制已在动物实验中得到证实，Kerr等[6]的研究显示，SHP基因敲除小鼠体内CYP7A1、CYP8B1水平较正常小鼠显著升高，胆汁酸合成增加。相反，持续表达SHP的转基因小鼠体内CYP7A1水平降低，胆汁酸合成减少[7]。

除SHP途径外，近年研究[8-10]还发现FXR激活后可诱导成纤维细胞生长因子15(FGF15)(鼠)和FGF19(人)表达，FGF15、19可激活肝FGF受体4(FGFR4)，启动JNK、ERK信号通路，导致CYP7A1基因表达下调。

2. 促进胆汁酸排泄：FXR对胆汁酸跨上皮转运、排入门静脉系统等过程具有调节作用。在肝细胞中，FXR可诱导胆盐输出泵(bile salt export pump, BSEP)生成，促进胆汁酸排入胆汁[11]。进食后，胆汁从胆囊排入十二指肠，胆汁酸在回肠段的重吸收由肠绒毛刷状缘上的顶端钠依赖性胆汁酸转运体(apical sodium-dependent bile acid transporter, ASBT)介导。研究[12-13]显示，FXR可抑制ASBT生成，并能上调肠上皮细胞中的回肠胆汁酸结合蛋白表达。Boyer等[14]的研究发现，FXR可诱导有机溶质转运体α/β(OSTα/β)生成，从而影响胆汁酸通过肠上皮细胞进入门静脉。综上，激活FXR可促进胆汁酸排泄，减轻肝内胆汁淤积。

3. 抗肝纤维化：诸多研究显示FXR与肝纤维化形成相关。肝纤维化主要由肝星状细胞激活分泌大量细胞外基质所致。研究[15-16]发现，FXR在人和大鼠肝星状细胞中均有表达。FXR活化可抑制肝星状细胞分泌Ⅰ型胶原蛋白、转化生长因子-β1等促纤维化因子，从而预防甚至逆转肝纤维化[16-18]。

综上所述，FXR活化可减少胆汁酸生成，促进胆汁酸排泄及其在肝脏内的生物转化，从而减轻PBC胆汁淤积。其抗纤维化作用对缓解PBC肝纤维化具有重要意义。

二、FXR激动剂在PBC中的应用

多项动物实验表明，激动FXR可改善肝内、外胆汁淤积，减轻肝脏由胆汁淤积所致的损伤[19-20]。近年来，科研机构和医药企业进行了大量研发工作，设计、筛选出多种能强效激动FXR的配体，并将其应用于以PBC为代表的胆汁淤积性肝病。诸多FXR激动剂中，奥贝胆酸(obeticholic acid, OCA)是目前研究最多且惟一已开展多期PBC临床试验并被证明安全有效的药物。OCA又名6-乙基鹅去氧胆酸，是人体胆汁酸中CDCA的衍生物，其激动FXR的活性是CDCA的100倍[21]。血清碱性磷酸酶(ALP)和胆红素水平与PBC患者的预后密切相关，ALP、胆红素水平低的患者生存期较长[22]，两者可作为判断PBC患者远期结局的标记物，有助于FXR激动剂治疗PBC研究的开展。

1. UDCA联合OCA：Hirschfield等[23]在对UDCA应答欠佳的165例PBC患者中开展了联合应用OCA的随机双盲临床试验，患者ALP>1.5～10倍正常值上限。该试验在维持UDCA治疗的基础上，将患者分为OCA组和安慰剂组，再根据OCA剂量进一步分为10、25、50 mg组，每天给药1次，持续3个月，记录血清ALP等指标的变化。结果显示OCA组ALP水平较试验前显著降低，OCA 10、25、50 mg组分别降低24%、25%和21%，而安慰剂组仅降低3%。对部分患者延长随访期限至1年后，OCA组 ALP水平仍较基线值降低[24]。瘙痒是OCA最常见的不良反应，存在剂量效应关系，其在OCA 10、25、50 mg组的发生率分别为47%、87%和80%，并导致部分患者退出试验[23]。

另一项Ⅲ期临床试验中，216例血清 ALP>1.67倍正常值上限的PBC患者被随机分为安慰剂组、OCA 5 mg组和OCA 10 mg组，同时继续应用原剂量UDCA治疗12个月，6个月后OCA剂量可从5 mg/d增至10 mg/d。主要终点指标为：ALP至少降低15%，胆红素降至正常范围内。最终意向性分析结果显示OCA 10 mg组、OCA 5 mg～10 mg组(OCA 5 mg 组部分患者增量至10 mg)和安慰剂组患者的达标率分别为47%、46%和 10%[25]。

2. 单用OCA：Kowdley等[26]开展了一项单用OCA治疗PBC的Ⅱ期临床试验。59例PBC患者被随机分为OCA 10 mg 组、OCA 50 mg 组和安慰剂组，疗程12周，主要终点指标为ALP。结果显示OCA 10 mg组、OCA 50 mg组ALP水平较治疗前分别降低44%和37%，而安慰剂组ALP水平升高0.4%。然而，瘙痒在OCA 50 mg组的发生率高达94%。

上述研究表明，FXR激动剂OCA联合UDCA或单独应用对PBC均能起到较好的治疗效果，可显著降低ALP等血清学指标，不良反应主要为瘙痒，可能系由激动G-蛋白耦合胆汁酸受体1(Gpbar1)所致[27]。但需注意的是，目前已开展的OCA临床试验多关注于实验室生化指标的改善，且随访时间较短，至于OCA能否改善PBC患者的临床症状、病理分期以及生存期等仍有待研究证实。

三、结语

除OCA外，还发现了包括“GW4064”在内的多个可强效激动FXR的配体，但研究仍处于药理学验证阶段或由于药代动力学、毒理学等问题而终止研究[28-29]，因此亟待研发安全、有效且能特异性激动FXR的药物。综上所述，以OCA为代表的具有显著抗胆汁淤积功效的FXR激动剂是未来PBC治疗领域的新突破点，有望为PBC患者尤其是对UDCA应答不佳的患者提供新的治疗途径。

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(2016-07-15收稿；2016-08-22修回)

Role of Farnesoid X Receptor in Treatment of Primary Biliary Cholangitis

ZHAOJian,LIWei,YAODingkang.

DepartmentofInternalMedicine,ChangzhengHospital,theSecondMilitaryMedicalUniversity,Shanghai(200003)

YAO Dingkang, Email: czyaodingkang@163.com

Primary biliary cholangitis (PBC) is a commonly seen cholestatic liver disease. Currently, ursodeoxy-cholic acid (UDCA) is the only drug approved for the effective treatment of PBC. However, up to 40% of PBC patients had poor response to UDCA. Farnesoid X receptor (FXR) can inhibit the synthesis of bile acid, regulating the transport of bile acid and playing a role in anti-hepatic fibrosis. This article reviewed the role of FXR in treatment of PBC.

Primary Biliary Cholangitis; Farnesoid X Receptor; Obeticholic Acid; Cholic Acid; Therapy

10.3969/j.issn.1008-7125.2017.02.011

*本文通信作者，Email: czyaodingkang@163.com