2015, Vol. 50
法尼醇X受体 (farnesoid X receptor,FXRα,NR1H4) 是核受体超家族的一员。1995年Seol等[1]发现一个与人类维甲酸X受体 (retinoic X receptor,RXR,NR2B1) 相互作用的蛋白,将其命名为维甲酸X受体相互作用蛋白14 (retinoic X receptor-interacting protein 14)。随后F orman等[2]发现其能够被法尼醇 激活,又重命名为FXR。1999年,人们发现胆汁酸是FXR的内源性配体[3,4]。FXR基因是一个高度保守的基因,因而在很多物种体内都发挥着重要作用。
FXR主要在肝脏、肠道、肾脏、肾上腺中高表达,在心脏、脂肪组织及血管中低表达[2],另外,在胰岛β细胞中也发现了FXR的存在[5]。人或小鼠FXRα由单基因编码,FXR基因共有11个外显子,有两个启动子,分布于外显子1和3。利用不同的启动子和mRNA选择性剪切,FXR编码产生4个FXRα亚型: FXRα1、FXRα2、FXRα3和FXRα4[6,7,8]。与FXRα1和FXRα2相比,FXRα3和FXRα4的mRNA更短且仅编码N端氨基酸序列; 在FXRα1和FXRα3中,毗邻DNA结合区 (DNA binding domain,DBD) 有一个4个氨基酸 (MYTG) 的插入序列,而FXRα2和FXRα4则不包含MYTG序列。尽管多数基因受4个FXRα亚型平等调节,如回肠胆汁酸结合蛋白 (ileum bile acid-binding protein,I-BABP),而syndecan-1、αA- crystallin及成纤维生长因子19 (-broblast growth factor 19,FGF19) 基因表达却对缺乏MYTG的
FXRα2和FXRα4更敏感[8]。然而,对于FXRα 4个 亚型的准确性及每个亚型对基因调节的生理作用仍然有待确定。在啮齿类和犬类中发现了第二个FXR基因 (Fxrβ,NR1H5),但Fxrβ在人类和灵长类中是一个假基因 (pseudogene)。故本文中FXR即代表FXRα。
与其他核受体一样,FXR首先与RXR结合形成二聚体,再结合到DNA上特异的FXR反应元件 (FXR response element,FXRE) 调节基因转录。FXRE包含两个AGGTGCA同源序列,这两个序列可被1个核苷酸分隔形成反向重复序列 (inverted repeats,IR1) 或被8个核苷酸分隔形成外翻重复序列 (everted repeats,ER8),或被4个核苷酸分隔形成直接重复序列 (direct repeats,DR4)[9,10]。此外,尽管罕见或偶然,FXR也能直接与DNA结合[11]。
到目前为止,对FXR的研究已经进行了十几年,发现FXR是一个多功能的核受体,其在维持胆汁酸代谢、脂质和糖稳态上扮演了重要的角色[12,13]。近些年也发现了FXR的一些新功能,包括肠道屏障保护作用,对先天性免疫的调节[14,15]以及在肿瘤发生中的调节作用[16,17]。本文将围绕FXR对胆汁酸代谢、糖脂代谢稳态及非酒精性脂肪肝的作用进行综述。
胆汁酸具有促进餐后脂肪和胆固醇在肠道消化吸收的作用。胆汁酸只能在肝脏由胆固醇合成,分泌进入胆小管,并储存在胆囊。食物摄入后可刺激十二指肠分泌胆囊收缩素 (cholecystokinin,CCK),CCK促进胆囊收缩,将胆汁排入肠腔,易消化饮食性脂肪形成微滴,易于肠道吸收。大约有95% 分泌入肠腔的胆汁酸在回肠末端被重吸收并转运至肝脏,形成胆汁酸的肠肝循环 (enterohepatic circulation)。而只有5% 胆汁酸随粪便排出体外。排出体外的胆汁酸及胆固醇代表了胆固醇从体内消除的全部形式[18,19]。
体内胆汁酸过高对细胞有毒害作用,而胆汁酸经肝肠循环重新回到肝脏可抑制其自身的合成,FXR在这一过程中发挥了重要作用。主要涉及3个途径: 小异二聚体伴侣 (small heterodimer partner,SHP,NR0B2) 途径、小鼠成纤维生长因子15 (fibroblast growth factor,FGF15))/人FGF19和c-Jun氨基末端激酶 (c-Jun N-terminal protein kinase,JNK) 途径。胆固醇7α-羟化酶 (CYP7A1) 是胆汁酸生物合成的限速酶。重吸收到肝脏的胆汁酸激活FXR,增加FXR直接靶基因SHP的表达,进而抑制CYP7A1及固醇12α-羟化酶 (sterol 12α-hydroxylase,CYP8B1) 的表达[12,13]。然而,在Shp-/-小鼠,胆汁酸仍然能够抑制CYP7A1的表达[20,21],表明胆汁酸对CYP7A1的转录抑制有其他不依赖于SHP的途径。FGF15 (人FGF19) 是由肠道分泌的一种生长因子,肠道FXR被胆汁酸激活后增加FGF15的表达并促进其通过肝肠循环进入肝脏,作用于肝脏中的FGFR4,激活JNK信号通路,抑制CYP7A1的表达,减少胆汁酸的生物合成,进而改善肝脏的胆汁淤积[22,23,24,25]。而Fgfr-/- 小鼠CYP7A1的表达增加,胆汁酸池增大,进一步表明FGF15与FGFR4表达增加抑制了胆汁酸的合成[26]。
FXR不仅能够通过抑制CYP7A1,抑制肝细胞胆汁酸的合成,促进胆盐的合成和排泄,降低肝细胞的胆汁酸毒性,FXR亦可通过降低胆汁酸在小肠黏膜上皮细胞的吸收,抑制胆汁酸的肠肝循环而进一步降低肝细胞的胆汁毒性。FXR能够调节胆汁酸代谢,包括合成、结合、分泌和吸收。因此,FXR是胆汁酸的一个重要感受器,在维持胆汁酸稳态方面具有举足轻重的作用。
胆汁酸能够调节人体脂质代谢,肝脏中胆汁酸量的减少可以降低肝脏低密度脂蛋白胆固醇 (low- density lipoprotein cholesterol,LDL-C) 水平,增加高密度脂蛋白胆固醇 (high-density lipoprotein cholesterol,HDL-C) 水平[27]。随着对FXR研究的深入,越来越多的证据表明,FXR对机体脂质代谢具有重要的调节作用。因此,FXR可能成为调节血脂及治疗非酒精性脂肪肝 (non-alcoholic fatty liver diseases,NAFLD) 的新靶点。
肝脏是脂质代谢最重要的器官,肝脏中甘油三酯的合成、摄取及消除失衡时容易导致肝脏脂质堆积,进而发展为脂肪肝。Fxr基因敲除的小鼠血浆和肝脏中甘油三酯含量均显著增加[28]。FXR对甘油三酯代谢的调节主要从以下几个通路: ① FXR-SHP-SREBP-1c通路。研究表明,FXR被胆汁酸激活后,上调SHP的表达,抑制与脂肪酸合成密切 相关的固醇调节元件结合蛋白1c(sterol regulatory element-binding protein 1c,SREBP1c) 的表达,改善糖尿病小鼠脂肪肝及高脂血症[29,30]; 而在Shp-/-小鼠中,胆汁酸或FXR激动剂GW4064并不能抑制SREBP-1c及其靶基因表达,也未表现出降低肝脏甘油三酯的作用[29]。因此,FXR可能通过激活FXR-SHP-SREBP-1c通路降低肝脏甘油三酯水平。然而,另有一些研究 结果与此并不一致。肝脏过表达SHP的转基因小鼠,SREBP-1c的mRNA水平升高,并出现肝脂肪变性[31]; Shp-/-小鼠喂以高脂饮食时,其肝脏甘油三酯水平降低[32]; Matsukuma等[33]研究发现,激活FXR虽然抑制SREBP-1c的表达,但并不抑制SREBP-1c靶基因脂肪酸合酶 (fatty acid synthase,FAS) 的表达。这些研 究结果又表明激活FXR降低肝脏甘油三酯水平不依赖于FXR-SHP-SREBP-1c通路。因此,激活FXR降低肝脏甘油三酯水平是否由FXR-SHP-SREBP-1c通路调节尚需进一步研究。② 配体激活FXR使极低密度脂蛋白受体 (very low-density lipoprotein receptor,VLDLR) 的表达增加,继而使脂蛋白脂酶 (lipoprotein lipase,LPL) 介导的甘油三酯水解增加,并激活多配体蛋白聚糖-1 (syndecan-1,SDC1),从而促进VLDL和富含甘油三酯的乳糜微粒清除,减少脂肪生成[34]。③ FXR通过抑制微粒体甘油三酯转运蛋白 (MTP) 和载脂蛋白B (apolipoprotein B,ApoB) 的表达,控制VLDL的合成[35] 。④ FXR还能够激活载脂蛋白C2 (ApoC2) 和载脂蛋白A4 (ApoA4)[36,37],且抑制载脂蛋白C3 (ApoC3)[38]及血管紧张素类似蛋白3 (angiopoietin-like protein 3,ANG PTL3)[30],继而激活LPL,使甘油三酯的清除能力增强。⑤配体激活FXR还可上调过氧化物酶体增 殖物激活受体α (perox isome proliferator- activated receptor α,PPARα) 的基因表达,促进脂肪酸的β氧化[39]。综上,配体激活FXR主要通过减少肝脏脂肪生成及分泌并增加血中富含甘油三酯 脂蛋白的清除,从 而降低血浆甘油三酯水平。
很多研究表明,FXR是胆固醇稳态的重要调节因子。Fxr基因敲除小鼠体内血浆总胆固醇水平和肝脏中胆固醇含量均显著增加[28],血浆LDL-C及HDL-C水平增加,肝脏胆固醇逆向转运 (reverse cholesterol transport,RCT) 的相关基因表达减少,尤其是与HDL-C清除有关的清道夫受体BI (scavenger receptor BI,SR-BI) [40]。而给予GW4064诱导SR-BI的蛋白表达[41],促进小鼠RCT过程,降低血浆HDL-C[42,43]。最近也有研究表明,胆汁酸或GW4064激活人或转基因小鼠FXR,能够通过增加胆固醇酯转运蛋白 (cholesterylester transfer protein,CETP) 的表达,降低血浆HDL-C,同时也证明了CETP为FXR的一个新靶点[44]。另外,激活FXR显著延缓并抑制Ldlr-/-和Apoe-/-小鼠动脉粥样硬化的发展[45,46]。但是也有研究报道显示不一致的结果,Zhang等[47]发现Fxr-/-和Ldlr-/-小鼠比Ldlr-/-小鼠主动脉粥样硬化程度有所减缓,作者推测 可能是在双基因敲除的小
鼠体内LDL-C的水平降低,但具体机制尚不清楚; 在高胆汁酸的患者体内,其FXR被激活,血浆LDL-C水平亦高于正常人[44]; Guo等[48]也发现Fxr-/-和Apoe-/-小鼠比Apoe-/-小鼠的动脉粥样硬化损伤程度轻。然而Hanniman等[49]的研究却表明Fxr-/-和Apoe-/-小鼠比Apoe-/-小鼠动脉粥样硬化损伤加重。因此,FXR对动脉粥样硬化的影响仍有待于进一步研究。
NAFLD是最常见的肝脏疾病之一,经常与2型糖尿病 (type 2 diabetes mellitus,T2DM) 共存,其发病机制目前尚不清楚,但其发病过程最初通常是甘油三酯在肝脏的异常堆积。如上所述,FXR可通过多条途径调节甘油三酯代谢,这些也是FXR在NAFLD发病中的部分机制。
最近有研究表明,在人肝细胞中,FXR亦能够抑制ChREBP (carbohydrate response element-binding protein) 的转录[50]。FXR激活后通过一个转录抑制 的机制抑制葡萄糖诱导的基因表达: 增加ChREBP对辅阻遏蛋白的募集,并促进ChREBP从ChORE (carbohydrate response elemnt) 解离。GW4064能够减弱高糖对肝细胞FAS和ApoC3的诱导作用。然而,FXR是否通过ChREBP调节糖脂代谢还需进一步的体内研究确定。有研究表明,醛酮还原酶AKR1B7 (aldo- keto reductase) 可能是FXR在肝脏和肠道的直接靶基因,腺病毒介导的db/db小鼠AKR1B7过表达可改善肝脂肪变性[51],因此,推测AKR 1 B7可能是FXR另一个靶点,介导FXR改善肝脏脂肪变性的作用。
另外也有研究发现,一个调节细胞碳水化合物和脂质代谢重要的细胞因子——FGF21是FXR的直接靶基因。胆汁酸或GW4064激活FXR后,增加肝脏FGF21的表达和分泌[52],促进FGF21介导的脂肪组织的脂肪动员及肝脏中脂肪酸氧化和酮体生成[53]。而且,FXR也能通过诱导肠上皮细胞分泌FGF19,上调肝脏FGF21的表达,促进肝脏中脂肪酸的消耗[52],降低肝脏甘油三酯水平[54]。另有报道[55]认为,FGF21通过抑制SREBP-1c而抑制肝脏内源性脂肪酸生成。因此,肝脏中FXR-F GF21通路可能是FXR激活改善脂肪肝的一个重要分子机制。
FXR选择性激动剂,如GW4064、INT-747和Way-362450,能够逆转不同NAFLD动物模型的脂 质代谢紊乱[30,41,56,57],而Fxr-/-小鼠则表现出明显增加血浆甘油三酯水平、VLDL产生和肝脂肪变性[58]。近期,也有研究发现,同为甲硫氨酸和胆碱缺乏 (methionine- and choline-de-cient,MCD) 的饲料喂 养的小鼠中,Fxr-/-小鼠肝脏甘油三酯水平低于野生型(WT) 小鼠,且Fxr敲除同时给予MCD饲料喂
养 (Fxr-/-/MCD) 的小鼠与以MCD饲料喂养的野生型 (WT/MCD) 小鼠相比,其肝脏脂肪变性的程度较轻[59]。进一步研究表明,Fxr-/-/MCD小鼠肝脏中含量高于生理浓度的胆汁酸,抑制了与脂肪酸摄取和甘油三酯堆积有关的基因表达,这可能是Fxr-/-/MCD小鼠比WT/MCD小鼠肝脂肪变性程度轻的原因[59]。
越来越多的证据表明,FXR对糖稳态的调节起到重要作用。给予小鼠FXR激动剂GW4064或胆汁酸,显著降低小鼠血糖水平,改善胰岛素敏感性[41,60],这一作用在3种不同的糖尿病动物模型 (db/db,ob/ob和KKAy小鼠) 上得到验证。研究认为,激活肝脏FXR可调节肝糖异生、糖原合成及提高胰岛素敏感性。
肝糖异生在糖稳态中发挥着重要作用。db/db小鼠肝脏过表达FXR后,血糖水平降低约50%,表明了肝脏FXR的重要作用。给予db/db或KKAy小鼠GW4064对血糖和游离脂肪酸 (FFA) 同样具有降低作用,同样处理的野生型小鼠的血糖亦降低[41]。给予FXR激动剂可能同时激活肠道、肝脏和肾脏的FXR。因此,对于FXR激活后降低血糖这一效应尚不能确定其靶组织。在一系列研 究中发现,FXR被胆汁酸激活后,降低糖异生作用基因PEPCK (phosphoenoyl pyruvate carboxykinase) 和葡糖6磷酸酶 (glucose-6-phosphatase,G-6-Pase) 以及果糖-1,6-二磷酸酶1 (fructose-1,6-bisphosphatase1,FBP1) 的表达[61,62],而另有研究发现,GW4064激活FXR后反而诱导PEPCK的表达[63],且在FXR缺陷的小鼠体内,PEPCK和G-6-Pase的表达均被抑制[61,64]。尽管这些研究结果仍存在矛盾和争议,但FXR对肝脏糖异生的调节作用不可忽视。
FXR激动后G-6-Pase的表达降低,表明肝糖原的合成也可能改变。激活FXR使GSK3β磷酸化,从而使啮齿类原代肝细胞和糖尿病db/db小鼠肝脏糖原合成增加,提高肝糖原含量[41]。与此结果一致,Fxr-/-小鼠的肝糖原含量降低。
胰岛素抵抗 (insulin resistance,IR) 是2型糖尿病 (T2DM) 的主要特征之一,良好的胰岛素敏感性是维持糖稳态的必要条件。肝脏胰岛素抵抗能促进糖异生,使空腹血糖升高,而外周组织胰岛素抵抗导致其从血液中摄取利用葡萄糖能力下降,从而使餐后血糖升高。在1型糖尿病和T2DM大鼠体内,FXR的表达降低,给予胰岛素后可逆转这一现象[65]。在FXR缺陷的小鼠体内,糖酵解和脂肪生成的基因 (如脂肪酸合酶Fasn、乙酰辅酶A羧化酶Acc) 表达增加[64]。另有报道表明,FXR缺陷导致小鼠外周胰岛素抵抗,糖处置能力降低,脂肪组织和骨骼肌胰岛素信号减弱,然而在肝脏中却呈现出不一致的结果[41,60,61]。反之,给予胰岛素抵抗ob/ob小鼠FXR激动剂GW4064可改善高胰岛素血症,改善糖耐量[60]。
最近研究表明,FXR激动剂obeticholic acid (OCA,INT-747) 可能会应用于治疗T2DM。在2期临床试验中,给予OCA可以增加胰岛素敏感性[66]。Ghebremariam等[67]也证明,INT-747上调Dahl大鼠肝脏DDAH1 (FXR的一个配体) 的表达,增强其胰岛素敏感性。
FXR除了在调节胰岛素敏感性方面发挥重要作用,也有报道其作用于胰腺调节葡萄糖刺激的胰岛素分泌[68,69],预防脂毒性[68]。因此,激活FXR可能对改善T2DM的高血糖和高血脂具有重要意义。
FXR在机体胆汁酸代谢及糖脂代谢的调节中均发挥了重要作用。激活FXR能够降低血脂及肝脂水平,降低T2DM实验动物模型及患者的血糖,改善胰岛素敏感性。已有研究表明,抗寄生虫药物伊维菌素 (ivermectin) 作为一个新发现的FXR配体[70],可以直接作用于FXR,降低血糖和血浆胆固醇水平,因其已经是FDA批准的临床药物,所以伊维菌素可能很快在临床上应用于糖脂异常疾病的治疗。本实验室也开始以FXR为靶点进行研究,且初步结果表明,高脂模型动物体内胆固醇降低和脂肪肝的改善可能确实与激活FXR有关,进一步的研究正在进行中。因此,FXR是治疗脂肪肝及T2DM的一个新靶点,研发以FXR为靶点的激动剂类新药具有良好的应用前景。
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