趙 健 李 偉 姚定康

第二軍醫(yī)大學(xué)附屬長(zhǎng)征醫(yī)院內(nèi)科教研室(200003)

·綜 述·

法尼醇X受體在原發(fā)性膽汁性膽管炎治療中的作用

趙 健 李 偉 姚定康*

第二軍醫(yī)大學(xué)附屬長(zhǎng)征醫(yī)院內(nèi)科教研室(200003)

原發(fā)性膽汁性膽管炎(PBC)是一種常見(jiàn)的膽汁淤積性肝病。熊去氧膽酸(UDCA)是目前惟一被批準(zhǔn)并能有效治療PBC的藥物，但高達(dá)40%的PBC患者對(duì)UDCA應(yīng)答不佳。法尼醇X受體(FXR)具有抑制膽汁酸合成、調(diào)控膽汁酸轉(zhuǎn)運(yùn)和抗肝纖維化的作用。本文就FXR在PBC治療中的作用作一綜述。

原發(fā)性膽汁性膽管炎； 法尼醇X受體； 奧貝膽酸； 膽酸； 治療

原發(fā)性膽汁性膽管炎(primary biliary cholangitis, PBC)是一種以肝內(nèi)小膽管破壞為特征的慢性膽汁淤積性肝病，最終導(dǎo)致肝纖維化并引起多種相關(guān)并發(fā)癥。熊去氧膽酸(UDCA)是目前惟一被批準(zhǔn)并能有效治療PBC的藥物，但高達(dá)40%的PBC患者對(duì)UDCA應(yīng)答不佳[1]。因此，亟待探尋其他能有效治療PBC的藥物。

法尼醇X受體(farnesoid X receptor, FXR)是第一個(gè)被證實(shí)為以膽汁酸為天然配體的核受體，具有抑制膽汁酸合成、調(diào)控膽汁酸轉(zhuǎn)運(yùn)和抗肝纖維化的作用。其廣泛分布于肝臟、腸道、腎臟等部位，因可被法尼醇及其相關(guān)分子激活而得名。隨著FXR作用機(jī)制的逐步揭示，F(xiàn)XR激動(dòng)劑的研發(fā)在PBC治療領(lǐng)域備受關(guān)注，且已取得一定的研究成果。本文就FXR在PBC治療中的作用作一綜述。

一、FXR的作用

1. 抑制膽汁酸合成：膽汁酸合成過(guò)程中需多種酶催化，其中膽固醇7α-羥化酶(CYP7A1)是合成反應(yīng)中的限速酶，而細(xì)胞色素P8B1(CYP8B1)是使鵝去氧膽酸(CDCA)羥基化為膽酸的關(guān)鍵酶。FXR激活后可上調(diào)小異二聚體伴侶(small heterodimer partner, SHP)表達(dá)，后者可抑制肝X受體(LXR)、肝受體同系物-1(LRH-1)、肝細(xì)胞核因子4α(HNF4α)等多種核受體基因轉(zhuǎn)錄[2-3]。LRH-1、HNF4α是正向調(diào)控CYP7A1、CYP8B1表達(dá)的因子[4-5]，因此FXR可通過(guò)SHP間接抑制膽汁酸合成限速酶的生成，從而抑制膽汁酸合成。此種調(diào)節(jié)機(jī)制已在動(dòng)物實(shí)驗(yàn)中得到證實(shí)，Kerr等[6]的研究顯示，SHP基因敲除小鼠體內(nèi)CYP7A1、CYP8B1水平較正常小鼠顯著升高，膽汁酸合成增加。相反，持續(xù)表達(dá)SHP的轉(zhuǎn)基因小鼠體內(nèi)CYP7A1水平降低，膽汁酸合成減少[7]。

除SHP途徑外，近年研究[8-10]還發(fā)現(xiàn)FXR激活后可誘導(dǎo)成纖維細(xì)胞生長(zhǎng)因子15(FGF15)(鼠)和FGF19(人)表達(dá)，F(xiàn)GF15、19可激活肝FGF受體4(FGFR4)，啟動(dòng)JNK、ERK信號(hào)通路，導(dǎo)致CYP7A1基因表達(dá)下調(diào)。

2. 促進(jìn)膽汁酸排泄：FXR對(duì)膽汁酸跨上皮轉(zhuǎn)運(yùn)、排入門(mén)靜脈系統(tǒng)等過(guò)程具有調(diào)節(jié)作用。在肝細(xì)胞中，F(xiàn)XR可誘導(dǎo)膽鹽輸出泵(bile salt export pump, BSEP)生成，促進(jìn)膽汁酸排入膽汁[11]。進(jìn)食后，膽汁從膽囊排入十二指腸，膽汁酸在回腸段的重吸收由腸絨毛刷狀緣上的頂端鈉依賴性膽汁酸轉(zhuǎn)運(yùn)體(apical sodium-dependent bile acid transporter, ASBT)介導(dǎo)。研究[12-13]顯示，F(xiàn)XR可抑制ASBT生成，并能上調(diào)腸上皮細(xì)胞中的回腸膽汁酸結(jié)合蛋白表達(dá)。Boyer等[14]的研究發(fā)現(xiàn)，F(xiàn)XR可誘導(dǎo)有機(jī)溶質(zhì)轉(zhuǎn)運(yùn)體α/β(OSTα/β)生成，從而影響膽汁酸通過(guò)腸上皮細(xì)胞進(jìn)入門(mén)靜脈。綜上，激活FXR可促進(jìn)膽汁酸排泄，減輕肝內(nèi)膽汁淤積。

3. 抗肝纖維化：諸多研究顯示FXR與肝纖維化形成相關(guān)。肝纖維化主要由肝星狀細(xì)胞激活分泌大量細(xì)胞外基質(zhì)所致。研究[15-16]發(fā)現(xiàn)，F(xiàn)XR在人和大鼠肝星狀細(xì)胞中均有表達(dá)。FXR活化可抑制肝星狀細(xì)胞分泌Ⅰ型膠原蛋白、轉(zhuǎn)化生長(zhǎng)因子-β1等促纖維化因子，從而預(yù)防甚至逆轉(zhuǎn)肝纖維化[16-18]。

綜上所述，F(xiàn)XR活化可減少膽汁酸生成，促進(jìn)膽汁酸排泄及其在肝臟內(nèi)的生物轉(zhuǎn)化，從而減輕PBC膽汁淤積。其抗纖維化作用對(duì)緩解PBC肝纖維化具有重要意義。

二、FXR激動(dòng)劑在PBC中的應(yīng)用

多項(xiàng)動(dòng)物實(shí)驗(yàn)表明，激動(dòng)FXR可改善肝內(nèi)、外膽汁淤積，減輕肝臟由膽汁淤積所致的損傷[19-20]。近年來(lái)，科研機(jī)構(gòu)和醫(yī)藥企業(yè)進(jìn)行了大量研發(fā)工作，設(shè)計(jì)、篩選出多種能強(qiáng)效激動(dòng)FXR的配體，并將其應(yīng)用于以PBC為代表的膽汁淤積性肝病。諸多FXR激動(dòng)劑中，奧貝膽酸(obeticholic acid, OCA)是目前研究最多且惟一已開(kāi)展多期PBC臨床試驗(yàn)并被證明安全有效的藥物。OCA又名6-乙基鵝去氧膽酸，是人體膽汁酸中CDCA的衍生物，其激動(dòng)FXR的活性是CDCA的100倍[21]。血清堿性磷酸酶(ALP)和膽紅素水平與PBC患者的預(yù)后密切相關(guān)，ALP、膽紅素水平低的患者生存期較長(zhǎng)[22]，兩者可作為判斷PBC患者遠(yuǎn)期結(jié)局的標(biāo)記物，有助于FXR激動(dòng)劑治療PBC研究的開(kāi)展。

1. UDCA聯(lián)合OCA：Hirschfield等[23]在對(duì)UDCA應(yīng)答欠佳的165例PBC患者中開(kāi)展了聯(lián)合應(yīng)用OCA的隨機(jī)雙盲臨床試驗(yàn)，患者ALP>1.5～10倍正常值上限。該試驗(yàn)在維持UDCA治療的基礎(chǔ)上，將患者分為OCA組和安慰劑組，再根據(jù)OCA劑量進(jìn)一步分為10、25、50 mg組，每天給藥1次，持續(xù)3個(gè)月，記錄血清ALP等指標(biāo)的變化。結(jié)果顯示OCA組ALP水平較試驗(yàn)前顯著降低，OCA 10、25、50 mg組分別降低24%、25%和21%，而安慰劑組僅降低3%。對(duì)部分患者延長(zhǎng)隨訪期限至1年后，OCA組 ALP水平仍較基線值降低[24]。瘙癢是OCA最常見(jiàn)的不良反應(yīng)，存在劑量效應(yīng)關(guān)系，其在OCA 10、25、50 mg組的發(fā)生率分別為47%、87%和80%，并導(dǎo)致部分患者退出試驗(yàn)[23]。

另一項(xiàng)Ⅲ期臨床試驗(yàn)中，216例血清 ALP>1.67倍正常值上限的PBC患者被隨機(jī)分為安慰劑組、OCA 5 mg組和OCA 10 mg組，同時(shí)繼續(xù)應(yīng)用原劑量UDCA治療12個(gè)月，6個(gè)月后OCA劑量可從5 mg/d增至10 mg/d。主要終點(diǎn)指標(biāo)為：ALP至少降低15%，膽紅素降至正常范圍內(nèi)。最終意向性分析結(jié)果顯示OCA 10 mg組、OCA 5 mg～10 mg組(OCA 5 mg 組部分患者增量至10 mg)和安慰劑組患者的達(dá)標(biāo)率分別為47%、46%和 10%[25]。

2. 單用OCA：Kowdley等[26]開(kāi)展了一項(xiàng)單用OCA治療PBC的Ⅱ期臨床試驗(yàn)。59例PBC患者被隨機(jī)分為OCA 10 mg 組、OCA 50 mg 組和安慰劑組，療程12周，主要終點(diǎn)指標(biāo)為ALP。結(jié)果顯示OCA 10 mg組、OCA 50 mg組ALP水平較治療前分別降低44%和37%，而安慰劑組ALP水平升高0.4%。然而，瘙癢在OCA 50 mg組的發(fā)生率高達(dá)94%。

上述研究表明，F(xiàn)XR激動(dòng)劑OCA聯(lián)合UDCA或單獨(dú)應(yīng)用對(duì)PBC均能起到較好的治療效果，可顯著降低ALP等血清學(xué)指標(biāo)，不良反應(yīng)主要為瘙癢，可能系由激動(dòng)G-蛋白耦合膽汁酸受體1(Gpbar1)所致[27]。但需注意的是，目前已開(kāi)展的OCA臨床試驗(yàn)多關(guān)注于實(shí)驗(yàn)室生化指標(biāo)的改善，且隨訪時(shí)間較短，至于OCA能否改善PBC患者的臨床癥狀、病理分期以及生存期等仍有待研究證實(shí)。

三、結(jié)語(yǔ)

除OCA外，還發(fā)現(xiàn)了包括“GW4064”在內(nèi)的多個(gè)可強(qiáng)效激動(dòng)FXR的配體，但研究仍處于藥理學(xué)驗(yàn)證階段或由于藥代動(dòng)力學(xué)、毒理學(xué)等問(wèn)題而終止研究[28-29]，因此亟待研發(fā)安全、有效且能特異性激動(dòng)FXR的藥物。綜上所述，以O(shè)CA為代表的具有顯著抗膽汁淤積功效的FXR激動(dòng)劑是未來(lái)PBC治療領(lǐng)域的新突破點(diǎn)，有望為PBC患者尤其是對(duì)UDCA應(yīng)答不佳的患者提供新的治療途徑。

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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