韓 換，高依莎，宋春艷，鄭建明

第二軍醫(yī)大學(xué)長(zhǎng)海醫(yī)院病理科，上海 200433

非酒精性脂肪性肝炎分子靶向治療進(jìn)展

韓 換，高依莎，宋春艷，鄭建明

第二軍醫(yī)大學(xué)長(zhǎng)海醫(yī)院病理科，上海 200433

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)是目前最常見(jiàn)的肝臟疾病，NAFLD包括單純性肝脂肪變(simple steatosis)和非酒精性脂肪性肝炎(non-alcoholic steatohepatitis，NASH)。NASH是NAFLD最嚴(yán)重的形式，可發(fā)展為肝纖維化、肝硬化、肝細(xì)胞癌等。目前，NASH的發(fā)病機(jī)制仍不清楚，可能與遺傳、環(huán)境、代謝或應(yīng)激反應(yīng)有關(guān)。NASH相關(guān)的慢性肝病正日益增加，因此，NASH的早期治療顯得非常重要。盡管臨床試驗(yàn)性治療NASH已經(jīng)進(jìn)行了幾十年，但是目前針對(duì)NASH還沒(méi)有一種確切的治療方法。隨著對(duì)NASH發(fā)病機(jī)制研究的深入，尋找新的治療藥物靶點(diǎn)已成為當(dāng)今世界上NASH研究的一大熱點(diǎn)。2012年歐洲肝病研究學(xué)會(huì)年會(huì)(EASL)上，法國(guó)教授Ratziu就目前有關(guān)NASH治療的新靶點(diǎn)做了專題報(bào)告，之后很多專家學(xué)者就NASH的分子靶向治療提出了多種設(shè)想。目前為了更好地了解NASH分子靶向治療，作者閱讀了大量的文獻(xiàn)及報(bào)道資料，概述NASH治療的靶點(diǎn)。

非酒精性脂肪性肝炎；分子靶向治療

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)是危害人類健康的重要慢性肝病之一，發(fā)病率逐年升高，當(dāng)前世界發(fā)病率約20%[1]。NAFLD包括單純性肝脂肪變和非酒精性脂肪性肝炎(non-alcoholic steatohepatitis，NASH)，其中NASH是NAFLD的重要亞型，可以進(jìn)展為肝纖維化、肝硬化、肝細(xì)胞癌[2]。然而目前NASH的發(fā)病機(jī)制仍不清楚，可能與遺傳、環(huán)境、代謝或應(yīng)激反應(yīng)有關(guān)[3]，在中國(guó)NASH已經(jīng)作為一種慢性肝病被廣泛研究。1986年路德維希等首次使用術(shù)語(yǔ)“非酒精性脂肪性肝炎”，并認(rèn)為NASH的組織學(xué)表現(xiàn)與酒精性脂肪性肝炎相似，不同的是NASH缺乏過(guò)量飲酒史[4]。有關(guān)NASH各方面的研究進(jìn)展，治療進(jìn)展研究最慢，過(guò)去大家并沒(méi)有把NASH作為一種疾病對(duì)待，認(rèn)為它是糖尿病或肥胖的一種良性并發(fā)癥，這種錯(cuò)誤的觀念導(dǎo)致了NASH作為一種疾病忽視了對(duì)其的診斷、研究和治療[5]。在美國(guó)，目前NASH是導(dǎo)致肝硬化的第三大危險(xiǎn)因素，由NASH原因?qū)е碌母我浦惨才旁诘谌唬疫@一比率還在快速上升[6]。NASH治療的意義是降低患者死亡率，減少肝及心血管等并發(fā)癥的發(fā)生與發(fā)展，減輕臨床癥狀和改善患者生活質(zhì)量等。為了更好地了解NASH的治療，本文搜集了最新文獻(xiàn)資料，報(bào)道了目前NASH治療的靶點(diǎn)及其制劑主要有：(1)選擇性外周大麻素受體(CB)阻制劑；(2)過(guò)氧化物酶體增殖物激活受體(PPAR)激動(dòng)劑；(3)半胱天冬酶(Caspase)抑制劑；(4)磷酸二脂酶4(PDE4)抑制劑；(5)其他，這些新的分子靶標(biāo)為NASH的治療開(kāi)辟了新的方向。

1 外周大麻素受體阻制劑

內(nèi)源性大麻素(endocannabinoid，EC)是脂類介質(zhì)，與大麻素受體結(jié)合產(chǎn)生類似大麻的效應(yīng)，從而調(diào)節(jié)人的食欲[7]。大麻素受體(CB)有兩種亞型：CB1和CB2。它們主要分布于腦組織中，少量CB1分布在肝臟和其他外周組織，少量CB2分布在免疫和造血組織[8]。大麻素還能調(diào)節(jié)外周組織的能量代謝，CB1介導(dǎo)的脂蛋白脂肪酶活性在脂肪細(xì)胞中增加，并刺激脂肪酸在肝細(xì)胞中的合成[9]。肝細(xì)胞中的大麻素越來(lái)越被認(rèn)為是導(dǎo)致脂肪肝的關(guān)鍵介質(zhì)，且和胰島素抵抗聯(lián)系緊密[10]。在脂肪組織和肝臟，CB1活化可以促進(jìn)脂肪堆積，研究[11]證實(shí)，NAFLD患者肝臟脂肪酸的合成增加。肝細(xì)胞中CB1受體的異常激活在許多肝臟炎性疾病中發(fā)揮了很大的作用，包括NAFLD、NASH、酒精性脂肪性肝炎、肝纖維化和肝硬化[12-13]等。在體外試驗(yàn)油酸誘導(dǎo)的人細(xì)胞NAFLD和NASH模型，使用CB1受體激動(dòng)劑可增加肝細(xì)胞內(nèi)脂質(zhì)沉積，加重肝細(xì)胞脂肪變的程度[14]。激活肝細(xì)胞CB1受體能刺激脂肪酸的從頭合成，增加肝臟胰島素抵抗，且CB1受體的高表達(dá)能夠?qū)е侣跃凭珨z入、高脂飲食、誘導(dǎo)肝纖維化，在這種條件下很容易導(dǎo)致肝硬化和肝癌[15]。因此，CB1受體拮抗劑可以作為治療NASH的一個(gè)新的靶點(diǎn)。

CB1受體拮抗劑可以提高ATP生成量，減少食物攝入，改善肝脂肪變性、胰島素抵抗、血脂異常和炎癥性肝病，并促進(jìn)體質(zhì)量減輕等[16]。利莫那班是首個(gè)選擇性CB1受體拮抗劑，能夠逆轉(zhuǎn)和預(yù)防肥胖Zucker大鼠的脂肪肝，并能夠顯著改善NASH患者脂類代謝和肝臟功能[17-18]。但是利莫那班因其精神副作用，最顯著的抑郁、焦慮和自殺意念等被撤離市場(chǎng)[19]。由于CB1受體只有少量分布在外周組織，其他大部分分布于腦組織，所以CB1受體拮抗劑對(duì)中樞神經(jīng)系統(tǒng)的副作用亟待解決。事實(shí)上，已有新的外周特異性CB1受體拮抗劑報(bào)道，如AM6545、TM38837、JD5037、SLV319[16，20]等。最新研究[21]發(fā)現(xiàn)VD60在外周血中濃度比中樞高，副作用小，表明VD60可作為一種新的外周特異性CB1R拮抗劑，有效地抑制NASH的進(jìn)展。關(guān)于CB2，最近研究[22]結(jié)果表明，其可能具有抗炎和抗纖維化作用，CB2受體激動(dòng)劑臨床研究目前仍在進(jìn)行。

2 PPAR激動(dòng)劑

PPAR核受體亞家族由3個(gè)成員組成：PPARα、PPARγ和PPARδ，在NAFLD的發(fā)病機(jī)制中起關(guān)鍵作用。PPARα是長(zhǎng)鏈脂肪酸的分子靶向藥物貝特類藥物的作用靶點(diǎn)，在組織中的高表達(dá)能夠分解代謝脂肪酸[23]。據(jù)報(bào)道下調(diào)PPARα能夠減少游離脂肪酸的分解代謝，從而引起NASH的發(fā)生、發(fā)展[24]。此外，PPARα與脂聯(lián)素受體2(AdipoR2)相關(guān)，活化AdipoR2能夠提高PPARα水平并激活PPARα通路，從而引起脂肪酸氧化并減少氧化應(yīng)激[25]。PPARα激動(dòng)劑非諾貝特和吉非貝齊能夠改善人類血脂水平和胰島素敏感性[26]。PPARγ在脂肪酸(FA)的分解代謝中起著舉足輕重的作用，通過(guò)上調(diào)線粒體的FA氧化基因、過(guò)氧化物酶FA氧化及其他方面的脂肪酸氧化等眾多基因表達(dá)參與FA的分解代謝[27]。噻唑烷二酮類(TZDs)是PPARγ受體激動(dòng)劑，能夠改善肝臟和外周胰島素敏感性，且TZDs減輕伴或不伴有NASH的2型糖尿病患者的肝臟脂肪變性，通過(guò)減少游離脂肪酸的堆積來(lái)減輕NAFLD患者的肝損傷[28]。然而，TZDs治療NASH備受爭(zhēng)議，因其副作用如體質(zhì)量增加、水腫、充血性心力衰竭、骨折、患膀胱癌可能等[29]。PPARδ高表達(dá)在線粒體功能、肌肉的發(fā)育、脂肪酸氧化和胰島素敏感性等中起著至關(guān)重要的作用[30]。用健康志愿者進(jìn)行為期2周的臨床研究試驗(yàn)，中度肥胖患者效果顯示，PPARδ激動(dòng)劑GW501516能降低空腹血漿甘油三酯，增加高密度脂蛋白水平，表明PPARδ激動(dòng)劑具有改善血脂的作用[31]。雙重PPARα/δ激動(dòng)劑GFT505是一種新型的肝靶向胰島素增敏劑，是治療2型糖尿病和NAFLD很有前景的候選藥物[32]。

另外研究[33]發(fā)現(xiàn)，在NASH患者體內(nèi)CB1和PPAR基因表達(dá)呈負(fù)相關(guān)關(guān)系，CB1高表達(dá)、PPARα低表達(dá)，說(shuō)明CB1是NAFLD的一個(gè)有害因素，PPAR高表達(dá)是有利因素。

3 Caspase抑制劑

肝細(xì)胞凋亡是很多肝臟疾病的一個(gè)重要發(fā)病機(jī)理，不僅在NAFLD，還包括病毒性肝炎、威爾遜氏病、膽汁淤積性肝病及酒精誘導(dǎo)的肝損傷等疾病，肝細(xì)胞凋亡已被公認(rèn)為是肝纖維化和肝硬化進(jìn)展的一個(gè)重要機(jī)制[34]。肝細(xì)胞凋亡加重炎癥反應(yīng)，凋亡小體活化肝星狀細(xì)胞，并促使其向肌纖維母細(xì)胞表達(dá)，從而導(dǎo)致肝臟膠原蛋白堆積引起肝組織損傷和肝臟纖維組織增生促進(jìn)肝纖維化[35]。NASH患者體內(nèi)死亡受體表達(dá)增加，尤其是Fas受體，NASH患者肝細(xì)胞的凋亡是通過(guò)激活Fas受體實(shí)現(xiàn)的，這和疾病的進(jìn)展緊密相連[36]。事實(shí)上已有報(bào)道[37]顯示在NASH患者中Fas受體表達(dá)上調(diào)。由于肝細(xì)胞凋亡是一種重要的炎癥和纖維化介體，抑制細(xì)胞凋亡可能是治療NASH的一種有效方法。從脂肪肝進(jìn)展為NASH的特征性標(biāo)志是肝細(xì)胞凋亡的程度，這表明抑制肝細(xì)胞凋亡，可以阻止NAFLD病程的進(jìn)展[38]。肝臟凋亡小體的累積和α-SMA表達(dá)增多是NASH患者隨后發(fā)生肝纖維化有用的預(yù)測(cè)指標(biāo)[39]。

細(xì)胞凋亡是一種程序性細(xì)胞死亡的過(guò)程，主要是通過(guò)蛋白酶家族的調(diào)節(jié)[40]。報(bào)道[34]顯示Caspase抑制劑能通過(guò)清除活化的肝星狀細(xì)胞有效延緩或減輕肝纖維化的進(jìn)程。VX-166是一種不可逆的pancaspase抑制劑，已被證實(shí)在急性肝損傷老鼠模型中能夠保護(hù)肝臟功能和降低死亡率[41]。最近一項(xiàng)報(bào)道[34]顯示VX-166治療NASH患者可以減少肝細(xì)胞凋亡，減輕炎癥的進(jìn)展，還能減慢肝纖維化的進(jìn)展。GS-9450是另一Caspase選擇性抑制劑，主要作用在肝臟，其安全性和效益還需大樣本臨床試驗(yàn)驗(yàn)證[42]。由于NASH患者肝臟長(zhǎng)期暴露于凋亡應(yīng)激的發(fā)生，許多殘存的肝細(xì)胞有更強(qiáng)的抗凋亡能力[43]。因此，Caspase抑制劑治療NASH可能會(huì)有更多的驚喜。

4 磷酸二脂酶(PDE)4抑制劑

PDE酶超家族包括11個(gè)或更多成員，它們不同于結(jié)構(gòu)、底物特異性、抑制劑選擇性、組織和細(xì)胞分布、激酶調(diào)節(jié)等[44]。炎細(xì)胞對(duì)抗炎性疾病機(jī)理首先是表達(dá)PDE4，PDE4抑制劑能夠增加細(xì)胞內(nèi)c-AMP的水平，并能夠減小炎癥細(xì)胞擴(kuò)散的范圍[45]。c-AMP有眾多的生理作用，阻止肝纖維化，減輕炎癥反應(yīng)，抑制巨噬細(xì)胞及中性粒細(xì)胞等的作用。細(xì)胞內(nèi)c-AMP的水平是通過(guò)PDE降解為50-環(huán)磷酸-磷酸腺苷來(lái)維持平衡的[46]。己酮可可堿是一種非選擇性PDE4抑制劑，能夠減少終末期肝硬化的一些致命的并發(fā)癥，如腦病、細(xì)菌感染，并能增加無(wú)并發(fā)癥的生存率[47]。選擇性PDE4抑制劑，能使c-AMP分解減少，提高c-AMP水平，發(fā)揮抗炎和抗纖維化作用。ASP9831是一種新的選擇性PDE4抑制劑，具有抗炎特性，主要針對(duì)活化的巨噬細(xì)胞、枯否細(xì)胞等，已在臨床試驗(yàn)中證明具有抗炎和抗纖維化作用[48]。其他PDE4抑制劑，如羅氟司特等藥物，安全性及有效性還待大樣本臨床試驗(yàn)來(lái)驗(yàn)證。

5 其他

RNA干擾是指高度特異性的一段沉默基因引發(fā)一段特異性mRNA降解，這可能代表了一種新的治療NASH方法。最新的研究[49]發(fā)現(xiàn)siRNA可用于NAFLD進(jìn)展為不可逆NASH的治療。

由于NAFLD的發(fā)病機(jī)制尚未完全闡明，其防治尚缺乏特異性手段。研究NASH新的治療方法的同時(shí)面臨著很多挑戰(zhàn)：發(fā)病機(jī)制非常復(fù)雜，缺少能完全模擬人類病理特征的NAFLD/NASH動(dòng)物模型，缺少一些能夠評(píng)價(jià)療效或治療應(yīng)答的無(wú)創(chuàng)的替代指標(biāo)等，目前在NASH領(lǐng)域最迫切的需要是發(fā)現(xiàn)特異性的生物標(biāo)志物，將有助于早期診斷和監(jiān)測(cè)疾病的進(jìn)展，達(dá)到早期治療NASH的效果。由于NASH常伴隨著代謝異常如高血壓、糖尿病、血脂異常、肥胖等，這些疾病的治療對(duì)于NASH患者同樣重要，所以對(duì)于NASH患者的管理不僅需要肝病專家，還需要內(nèi)分泌專家、心血管疾病專家等多學(xué)科專家管理，多學(xué)科療法是一種選擇，但是大數(shù)據(jù)的研究是迫切期待的。NASH和NASH相關(guān)疾病的進(jìn)展途徑多樣化，為了為個(gè)體化治療策略提供理論基礎(chǔ)，接下來(lái)的研究方向是確定新的治療靶點(diǎn)，根據(jù)NASH疾病嚴(yán)重程度來(lái)制定個(gè)體化治療。

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(責(zé)任編輯：王全楚)

Advances in molecular targeted therapy of non-alcoholic steatohepatitis

HAN Huan,GAO Yisha,SONG Chunyan,ZHENG Jianming

Department of Pathology,Changhai Hospital of Second Military Medical University,Shanghai 200433,China

Non-alcoholic fatty liver disease (NAFLD) is currently the most common liver disease. It encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) which can progress to liver fibrosis,cirrhosis and hepatocellular carcinoma. However， the pathogenesis of NASH remains unclear and is possibly related with heredity,environment,metabolism and stress. The increasing prevalence has resulted in NASH-related chronic liver disease. Therefore,early treatment is quite important. Despite decades of clinical trials,no single treatment can be recommended to all patients with NASH. With the in-depth study of the pathogenesis of NASH,the search for new molecularly targeted therapy has become a hot topic of current research. In the 2012 annual meeting of the European Association for the Study Liver (EASL),the France professor Ratziu did a special report about the treatment of NASH. Some experts and scholars had made a lot of visions on the molecular targeted therapy of NASH. To better understand the current treatments of NASH,the latest information and literatures were collected and the current target for the treatments of NASH and its preparations were reported.

Non-alcoholic steatohepatitis; Molecular targeted therapy

國(guó)家自然科學(xué)基金(81500438)

韓換，碩士，E-mail：hhuan1992@163.com

鄭建明，教授，主任醫(yī)師，博士生導(dǎo)師，E-mail：jmzheng1962@163.com

10.3969/j.issn.1006-5709.2016.04.005

R575.5

A

1006-5709(2016)04-0378-04

2016-03-31