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Pharmacy Information
Vol. 11  No. 03 ( 2022 ), Article ID: 51123 , 7 pages
10.12677/PI.2022.113020

成纤维细胞生长因子19/15的表达调节与 生物活性

白玉洁，戴岳*

中国药科大学，江苏 南京

收稿日期：2022年4月6日；录用日期：2022年5月3日；发布日期：2022年5月10日

摘要

FGF19(啮齿动物中FGF15)是内分泌FGF家族的成员之一，属于肠道激素，参与调节胆汁酸、葡萄糖和脂质代谢等，维持全身稳态。FGF19/15对多种慢性疾病具有治疗潜力，包括肥胖症、糖尿病和恶性癌症等。本文总结FGF19/15的表达调节及药理活性的研究进展，初步评估其临床应用潜力。

关键词

FGF19/15，胆汁酸稳态，糖脂代谢

Expression Regulation and Bioactivity of Fibroblast Growth Factor 19/15

Yujie Bai, Yue Dai*

China Pharmaceutical University, Nanjing Jiangsu

Received: Apr. 6th, 2022; accepted: May 3rd, 2022; published: May 10th, 2022

ABSTRACT

FGF19 (FGF15 in rodents), a member of the endocrine FGF family, is an intestinal hormone involved in the regulation of bile acid, glucose and lipid metabolism to maintain systemic homeostasis. FGF19/15 has the potential to treat a variety of chronic diseases, including obesity, diabetes and malignant cancers. This paper reviews the biological activities of FGF19/15, and preliminarily evaluates the clinical application.

Keywords:FGF19/15, Bile Acid Homeostasis, Metabolism of Glucose and Lipid

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

1999年，成纤维细胞生长因子19 (Fibroblast growth factor, FGF19)在人脑中首次被发现，其编码基因位于染色体11q13，由216个氨基酸组成，在回肠和胆囊上皮细胞中高表达 [1]，但在正常肝脏中检测不到 [2]。成年小鼠的回肠、空肠和十二指肠中高度表达FGF15，是FGF19的小鼠同源物，由218个氨基酸组成，与人FGF19具有51%的相似性。与其他具有旁分泌和自分泌功能的FGF不同，FGF19/15对硫酸乙酰肝素蛋白聚糖(HSPG)的亲和力低，这使得它们在细胞中合成后分泌进入细胞外基质，并且作为内分泌激素参与循环 [3]。除了在调节胆汁酸稳态中的核心作用外，FGF19对代谢性疾病(如肥胖和糖尿病)亦具有治疗潜力 [4]。

本文总结FGF19/15表达的调控信号及生物活性，对其潜在的临床应用前景进行分析。

2. FGF19/15表达的调控因素及信号传导

FGF19基因的启动子区含有功能性法尼醇X受体反应元件(FXRE)，当胆汁酸作用于法尼醇X受体(FXR)后，FXR与FXRE结合，诱导FGF19/15在回肠上皮细胞中表达。最近的研究表明，FGF19/15表达还受到其他成分错综复杂的调节，如：1) 甾醇调节元件结合蛋白2 (SREBP2)通过抑制FXR与FGF19启动子中的FXRE结合，负性调控肠癌细胞中FGF19的转录 [5]；2) 核受体维生素D受体(VDR) [6]、类视黄醇X受体(RXR)和孕烷X受体(PXR) [7] 等均可诱导小鼠肠道中FGF15表达；3) 新发现的肠道蛋白包含的甲基多巴-A5-酪氨酸磷酸酶(MAM)和低密度脂蛋白(LDL)受体A类结构域1 (MALRD1)能促进FGF19/15转录 [8]；4) Wnt调节转录因子TCF7L2基因的转录也能上调小鼠肠道中FGF15表达水平 [9]。

分泌的FGF19/15与首选受体FGFR4和辅助受体β-klotho结合 [10]，募集细胞溶质接头蛋白(如支架蛋白—成纤维细胞生长因子受体底物2α (FRS2α))，从而触发信号级联反应，呈现抑制肝胆汁酸合成等作用。虽然肝脏是FGF19激活FGFR4-β-klotho复合物信号传导的主要部位，但FGF19在其他组织中也有多重生物学功能，在白色脂肪组织(WAT)，FGF19结合并激活其中的FGFR1c-β-klotho [11]。细胞外信号调节激酶1 (ERK1)、ERK2和原癌基因Ras-ERK-p90等下游信号可介导FGF19-FGFR4-β-klotho复合物的作用 [12] [13]。

3. FGF19/15的生物活性

3.1. 调控胆汁酸稳态

胆汁酸是肝脏中胆固醇分解代谢产生的强清洁剂，具有强乳化作用和毒性，其合成须受到严格调控。餐后胆囊收缩，将胆汁酸释放到肠道中，协助脂质和脂溶性维生素溶解和吸收 [14] [15]。FXR刺激FGF19/15在小肠中表达，后者通过靶向FGFR4和孤核受体小异源二聚体伴侣(SHP)抑制肝脏中的胆固醇7α-羟化酶(CYP7A1)活性和表达，该酶负责催化经典胆汁酸合成途径中的第一步和限速步骤。

在化学诱导的胆汁淤积性肝损伤模型小鼠回肠中FGF15表达降低 [16]。缺乏FGF15的小鼠肝脏中CYP7A1 mRNA和蛋白水平增加，CYP7A1酶活性和粪便胆汁酸排泄相应增加。Fgf15−/−、Fgfr4−/−和β-klotho−/−敲除动物的胆汁酸代谢失调，而在Fgfr4−/−和β-klotho−/−敲除动物中使用人源FGF19未能抑制CYP7A1表达 [11]。而给予FGF19能够降低人原代肝细胞中CYP7A1的mRNA表达水平，给予胆汁酸或FXR激动剂诱导小鼠回肠上皮细胞表达FGF15，能够抑制肝脏中CYP7A1表达，阻止胆汁酸的合成 [17]。

NGM282是FGF19合成衍生物，其对肝脏疾病尤其是胆汁淤积性肝病具有改善作用 [18]。患有胆汁淤积性肝病的患者使用NGM282后，降低了具有高细胞毒性和去污活性的甘氨酸结合型疏水性胆汁酸表达水平，这为NGM282治疗胃肠道和肝脏疾病提供了可能 [19]。此外，FGF19类似物的辅助治疗也能够改善对熊去氧胆酸(UDCA)治疗无反应的原发性胆汁型肝硬化患者的疾病症状 [4]。

3.2. 调节糖脂代谢

3.2.1. 对糖代谢的影响

除了调节胆汁酸稳态外，FGF19/15参与维持糖代谢 [20]，代谢综合征或二型糖尿病患者的循环FGF19水平低于健康对照组 [21]。Fgf15基因敲除小鼠不能正常维持血液中的葡萄糖浓度，并表现出肝糖原水平降低和葡萄糖耐受不良的现象，而这些可通过外源性给予FGF19的方式得到改善 [12]，而给予Fgfr4敲除小鼠FGF15并不能起到类似作用。

腺相关病毒(AAV)过表达FGF15可增加饮食诱导的肥胖(DIO)小鼠的能量消耗，限制db/db小鼠糖尿病的发生 [22]。在胰岛素抵抗的小鼠模型中，脑室内注射FGF19可改善血糖状态并增强外周胰岛素信号传导，改善糖尿病大鼠的葡萄糖代谢 [23]。静脉注射FGF19可降低DIO和ob/ob小鼠的体重，提高葡萄糖利用率 [24]。机制上FGF19/15通过抑制环磷酸腺苷(cAMP)反应元件结合蛋白–过氧化物酶体增殖物激活受体-γ共激活剂-1α (CREB-PGC-1α)信号传导，抑制葡萄糖的肝脏代谢 [25]。

3.2.2. 对脂质代谢的影响

FGF19/15在调节脂质代谢中同样起着重要作用。肥胖患者血液中的FGF19浓度低于健康受试者 [4] [26]，非酒精性脂肪肝疾病(NAFLD)患者血清的FGF19浓度降低 [27]。

Fgf15敲除降低HFD诱导的小鼠血清甘油三酯增加以及脂质代谢酶基因的表达，表明FGF15改善了小鼠脂质代谢 [28]。人源FGF19可降低小鼠体重，防止小鼠脂肪沉积，降低丙氨酸氨基转移酶(ALT)活性和肝脏脂质(如甘油三酯和游离脂肪酸)水平，增加肝脏脂肪酸氧化 [29]。长效的FGF19/载脂蛋白嵌合分子治疗可减少小鼠体内肝脏脂质积累 [30]，证明FGF19及其类似物可改善代谢性疾病模型非酒精性脂肪性肝炎(NASH)的病理学特征，呈现抗脂质蓄积、抗炎和抗纤维化的作用 [31] [32]。

目前，NGM282的I期安全性和耐受性研究以及NASH患者中为期12周的II期安全性、耐受性和有效性研究已经完成 [33]。II期临床的研究结果与临床前动物研究的结果大体一致，NGM282能够降低体重和身体质量指数(BMI)。肝活检的组织学评估发现，84%的患者疾病活动性评分(NAS评分)有所改善，42%的患者的纤维化分期有所改善。II期研究结果与临床前动物研究的主要区别在于给药后血脂水平差异 [34]。24周后，接受NGM282治疗的NASH患者肝脏脂肪含量显著降低，并伴随纤维化程度的改善 [35]。

机制研究发现，FGF19显著降低与脂肪生成相关基因的转录水平，包括乙酰辅酶A羧化酶(ACC)、血小板糖蛋白4 (CD36)、转录因子甾醇调节元件结合蛋白-1c (SREBP-1c)、硬脂酰辅酶A1 (SCD1)和CYP7A1 [29]。另外，在FGFR1c/KLB敲除小鼠中，FGF19缺乏代谢活性，表明FGF19可依赖FGFR1c/KLB表达降低肝脂肪变性 [36]，而肝脏FGFR4对于FGF19改善高脂肪饮食喂养小鼠的脂质代谢可能并不是必需的 [37]。

棕榈酸是一种在动物及植物内普遍存在的脂肪酸，过量的棕榈酸会抑制葡萄糖摄取，增加胰岛素抵抗，上调线粒体β-氧化，导致线粒体过载，增加活性氧(ROS)产生。给予FGF19可抑制小鼠成肌细胞的棕榈酸酯β-氧化，减轻线粒体过载并防止线粒体介导的细胞凋亡 [38]。FGF19促进线粒体中PGC1α、线粒体转录因子A (TFAM)、血红素加氧酶1 (HO-1)等表达，改善棕榈酸诱导的线粒体功能障碍 [39]。

3.3. 促进有丝分裂作用

FGF15在小鼠具有促进有丝分裂活性，能够诱导肝细胞增殖，在促进肝再生方面至关重要，Fgf15缺乏的小鼠经历肝切除术之后表现出肝再生受损、明显的肝损伤和更高的死亡率 [40]，这种活性导致FGF19/15可能与肝细胞性肝癌(HCC)相关。FGF15的异位表达促进肝细胞增殖、发育异常和肿瘤形成，这种致癌作用与FGFR4密切相关，FGFR4缺失或使用FGFR4中和抗体能够减少小鼠异位FGF19表达后的肿瘤负荷 [41]。靶向FGF19-FGFR4通路可有效抑制临床前动物模型中HCC的发展。FGF19也可能是肺鳞状细胞癌(LSQ)的有效标志物和潜在驱动因素 [42]，非小细胞肺癌患者的血清FGF19水平明显高于对照组。在LSQ的小鼠体内模型中，FGF19的过表达促进了肿瘤细胞的增殖和迁移 [43]。

鉴于FGF19的致癌潜能，基于结构–功能原理对其进行改构十分必要。已有报道通过诱变FGF19的五个N端和肝素结合区，分离FGF19的有丝分裂活性和代谢活性，合成了一系列FGF19变体，它们保留了有益的代谢调节作用，减少了致癌性 [44]。

3.4. 其他

给予重组FGF19蛋白可以升高小鼠骨骼肌质量和强度，增加人肌肉细胞在从成肌细胞分化为肌管过程中的肌管面积 [45]。FGF19通过上调肌肉细胞生长的关键调节剂核糖体蛋白S6激酶(S6K1)的磷酸化水平增强肌肉纤维，改善小鼠肌肉萎缩的症状 [46]。

冠状动脉疾病(CAD)是一种缺血性心脏病，包括稳定型心绞痛、不稳定型心绞痛、心肌梗死和心源性猝死。血清FGF19/15水平与CAD的存在和严重程度呈负相关。Fgf15基因敲除小鼠存在心脏缺陷、主动脉和肺动脉干排列不良等症状，这种情况与心室流出道早期发育的形态缺陷相关，表明FGF19/15是心室流出道发育所必需的 [47]。

4. 结语

自发现以来，几项突破性研究使人们对FGF19/15的功能和疾病治疗潜力有了更深入的了解。但基于FGF19的疗法面临的主要问题是：1) 存在潜在的脱靶效应；2) 天然FGF19蛋白分子量较小(约25 kDa)，通过肾脏后被迅速过滤清除，导致其半衰期短(约30 min) [20]，药代动力学性质较差；3) FGF19/15具有的致癌潜能 [48]。

针对FGF19/15成药受阻的原因，需对其进行有目的性的改构，同时考虑FGF19的药效机制与抑制FGF19-FGFR4通路，分离其调节代谢活性区域与致癌活性区域，对后者进行结构改变，避免潜在的不利影响。NGM282是FGF19的非致癌性变体，尽管其长期治疗的有效性和安全性仍需要进一步验证，目前认为它是最有希望的基于FGF19的内分泌干预手段。

总之，FGF19/15是调节代谢和器官间信号传导的重要激素，可作为疾病的危险因素和生物标志物。目前，靶向FGF19疗法(使用FGF19类似物或使用FXR激动剂)已取得较好的成果，而针对肠道疾病相关的FGF19缺乏症的治疗途径有待开拓。

文章引用

白玉洁,戴 岳. 成纤维细胞生长因子19/15的表达调节与生物活性
Expression Regulation and Bioactivity of Fibroblast Growth Factor 19/15[J]. 药物资讯, 2022, 11(03): 161-167. https://doi.org/10.12677/PI.2022.113020

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    49. NOTES

    *通讯作者。

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