CN109303921B - Fxr激动剂与sirt1激动剂联用在制备抗肝纤维化药物中的应用 - Google Patents
Fxr激动剂与sirt1激动剂联用在制备抗肝纤维化药物中的应用 Download PDFInfo
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- CN109303921B CN109303921B CN201811274825.7A CN201811274825A CN109303921B CN 109303921 B CN109303921 B CN 109303921B CN 201811274825 A CN201811274825 A CN 201811274825A CN 109303921 B CN109303921 B CN 109303921B
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Abstract
本发明公开了FXR激动剂与SIRT1激动剂联用在制备抗肝纤维化药物中的应用。相对于现有技术，本发明公开了FXR激动剂和SIRT1激动剂的联用在制备抗肝纤维化药物中的应用。在肝损伤状态下，FXR表达水平显著降低，而SIRT1激动剂可以显著抑制FXR蛋白下降，因此，本发明将FXR激动剂和SIRT1激动剂联合用于肝纤维化的治疗，具有重要意义。
Description
技术领域
本发明涉及FXR激动剂与SIRT1激动剂联用在制备抗肝纤维化药物中的应用，属于药物新用途技术领域。
背景技术
肝脏疾病尤其是病毒性肝炎、脂肪肝病、肝纤维化和肝癌等，在全球范围的发病率居高不下。如NAFLD在欧美普通成年人中的发病率为20-33％，肥胖人群中发病率达60-90％；在中国普通成年人患病率约为15％(Fan J G,Farrell G C.Epidemiology of non-alcoholic fatty liver disease in China.Journal of hepatology,2009,50(1):204-10.)。肝纤维化(Fibrosis)是一种病理状态，是指肝脏纤维结缔组织的过渡沉积。肝纤维化是慢性病毒性肝炎、代谢紊乱和慢性酒精性/非酒精性脂肪肝等慢性肝脏疾病进一步向肝硬化发展的中间环节，肝纤维化是慢性肝病的共同重要特征，且25-40％的慢性肝病患者最终发展为肝硬化甚至是肝癌。近几年的研究表明，肝纤维化是一个可以逆转的病变，而肝硬化是不可逆性病变。因此，抑制、阻止并逆转肝纤维化是治疗各种慢性肝病的中心环节。
抗肝纤维化药物的研发是当前肝药的研发热点，同时也取得了一定的研究进展。当前申报的防治肝纤维化相关的治疗药物主要有以下几类：1)中草药及其提取物，如姜黄、白藜芦醇、水飞蓟宾、别隐品碱及其盐(授权公告号CN10132721B)；2)化学药物及其制剂，如吡非尼酮和肌酐组合物(授权公告号CN103550242B)、闭花木酮Cleistanone衍生物(授权公开号CN104095857B)；3)生物制剂，包括重组蛋白和基因药物等，前者包括TGFβ1-抑制肽(授权公告号CN1203091C)和IL-4(授权公告号CN101318013B)等。尽管治疗的药物很多，但是目前尚未发现对肝纤维化的特效药物。因此，寻找确切有效的抗肝纤维化药物是今后努力发展的方向。
法尼醇X受体(Farnesoid X Receptor，FXR)又称NR1H4(Nuclear ReceptorSubfamily 1，Group H，Member 4)，是核受体超家族的一员。自1995年被克隆以来，该受体越来越多的功能被认识：FXR不仅在胆汁酸、脂质和糖代谢等生理过程中发挥重要作用，同时对多种病理进程具有调控作用：FXR通过FXR-FGF15/19信号通路介导了胆汁酸的促肝再生作用；FXR通过FXR/NF-κB负反馈环发挥抗炎作用(Wang Y D,Chen W D,Wang M,etal.Farnesoid X receptor antagonizes nuclear factor kappaB in hepaticinflammatory response.Hepatology,2008,48(5):1632-43.)；FXR通过阻断CREB-CRTC2复合体形成并抑制下游自噬相关基因表达进而发挥抗自噬作用(Seok S,Fu T,Choi SE,etal.Transcriptional regulation of autophagy by an FXR-CREB axis.Nature 2014；516:108-U274.)；另外FXR与肝脏肿瘤的形成密切相关：FXR-/-小鼠正常饲养至15个月时全部自发性发生肝脏肿瘤，而同龄野生型小鼠未见同样变化(Yang F,Huang X,Yi T,etal.Spontaneous development of liver tumors in the absence of the bile acidreceptor farnesoid X receptor.Cancer Res 2007；67:863-867.)。上述研究表明，FXR与肝脏疾病的发生发展密切相关。FXR激动剂是保肝抗纤维化药物的主要研究策略，有大量相关的专利申报(Wang H,He Q,Wang G,et al.FXR modulators for enterohepatic andmetabolic diseases.Expert Opin Ther Pat.doi:10.1080/13543776.2018.)，如CN201210482982.3(申请号)提供了细格菌素类化合物及其药学上可接受的盐在制备治疗FXR介导疾病药物中的应用，CN201180067346.8和CN201080043283.8(申请号)公开了FXR活性调节剂在药物组合物中的应用，均已被授权。另外，6E-CDCA(又称奥贝胆酸)作为一种强FXR激动剂，其抗NASH药效正在进行临床III期研究，作为抗原发性胆汁性肝硬化(PBC)药物已于2016年5月被美国FDA批准上市(Markham A,Keam SJ.Obeticholic Acid:FirstGlobal Approval.Drugs.2016Aug；76(12):1221-6.)，成为以FXR为靶点成功上市的第一例药物。
前期部分动物实验结果表明，OCA等FXR激动剂对于肝纤维化具有显著的疗效(Fiorucci S,Antonelli E,Rizzo G,et al.The nuclear receptor SHP mediatesinhibition of hepatic stellate cells by FXR and protects against liver fibrosis.Gastroenterology.2004Nov；127(5):1497-512.Fiorucci S1,Rizzo G,Antonelli E,et al.A farnesoid x receptor-small heterodimer partner regulatory cascademodulates tissue metalloproteinase inhibitor-1and matrix metalloproteaseexpression in hepatic stellate cells and promotes resolution of liverfibrosis.J Pharmacol Exp Ther.2005Aug；314(2):584-95.)；然而近期的两项临床研究结果显示：与安慰剂相比较，OCA对患者的肝纤维化指标并没有显著的改善作用(Nevens F,Andreone P,Mazzella G,et al.A Placebo-Controlled Trial of Obeticholic Acid inPrimary Biliary Cholangitis.N Engl J Med.2016Aug 18；375(7):631-43；Kowdley KV,Luketic V,Chapman R,et al.A randomized trial of obeticholic acid monotherapyin patients with primary biliary cholangitis.Hepatology.2018May；67(5):1890-1902.)。OCA在临床中失效的一个重要原因是OCA的作用靶点FXR在肝损伤患者的肝脏中表达水平显著下调，这进而导致了OCA无法显著激活FXR通路进而发挥抗纤维化作用。
发明内容
发明目的：为解决上述技术问题，本发明提供FXR激动剂与SIRT1激动剂联用在制备抗肝纤维化药物中的应用，并且通过试验证实，FXR激动剂与SIRT1激动剂联用具有显著增强的抗纤维化作用。
技术方案：为了实现上述发明目的，本发明采用以下技术方案：
FXR激动剂和SIRT1激动剂的联用在制备抗肝纤维化药物中的应用。
优选的：
所述FXR激动剂包括所述FXR激动剂包括各种结构类型的激动剂，并包括天然来源的(鹅去氧胆酸CDCA等)、半合成的以及全化学合成(GW4064和Fexaramine等)的激动剂。更优选地，所述FXR激动剂选自奥贝胆酸。
所述FXR激动剂能够促进FXR转录激活，促进其下游SHP、BSEP、OSTβ等靶基因的转录，抑制CYP7A1等靶基因的转录。
所述SIRT1激动剂包括各种结构类型的激动剂，并包括天然来源的、半合成的以及化学合成的激动剂，包括白藜芦醇、SRT1720等。
所述SIRT1激动剂能够促进蛋白的去乙酰化。
所述SIRT1激动剂为蛋白质乙酰化过程的任意环节、任意酶的激动剂。更优选地，所述SIRT1激动剂选自SRT1720。
在所述应用中，FXR激动剂与SIRT1激动剂以任意剂量/比例联用，均可达到抗肝纤维化的目的。
所述药物是以FXR激动剂与SIRT1激动剂作为仅有的成分所制成的药物。
或者，所述药物是以FXR激动剂与SIRT1激动剂作为活性成分，加上药学上可接受的辅料所制成的药物。
本发明所述药学上可接受的辅料，是指制备不同剂型时加入所需的各种常规辅料，例如稀释剂、黏合剂、崩解剂、助流剂、润滑剂、矫味剂、包合材料、吸附材料等以常规的制剂方法制备成任何一种常用的口服制剂，例如可以是颗粒剂、散剂、片剂、胶囊剂、丸剂、口服液、汤剂、滴丸剂等。
奥贝胆酸(OCA)在临床中失效的一个重要原因是OCA的作用靶点FXR在肝损伤患者的肝脏中表达水平显著下调，这进而导致了OCA无法显著激活FXR通路进而发挥抗纤维化作用。因此，阻断病理状态下FXR的表达下调，是OCA等FXR激动剂能够充分发挥药效的前提和重要保证。因此，本发明研究发现疾病状态下FXR蛋白降解，而SIRT1激动剂可以阻断FXR的降解，且在CCl4诱导的肝纤维化状态下，SIRT1激动剂与FXR激动剂的联用可以发挥显著增强的抗纤维化作用，为靶向FXR的新的肝纤维化的治疗策略。
技术效果:相对于现有技术，本发明公开了FXR激动剂和SIRT1激动剂的联用在制备抗肝纤维化药物中的应用。在肝损伤状态下，FXR表达水平显著降低，而SIRT1激动剂可以显著抑制FXR蛋白下降，因此，本发明将FXR激动剂和SIRT1激动剂联合用于肝纤维化的治疗，具有重要意义。
附图说明
图1：肝细胞损伤状态下FXR蛋白下降。
图2：SRT1720可以上调FXR表达。
图3：OCA与SRT1720联用对CCl4诱导的肝纤维化状态下肝脏FXR蛋白表达的作用。
图4：OCA与SRT1720联用对CCl4诱导的肝纤维化状态下肝脏FXR信号通路的作用。其中A为Fxr mRNA表达水平分析；B为Shp mRNA表达水平分析。*P<0.05，**P<0.01，***P<0.001。
图5：OCA与SRT1720联用对CCl4诱导的肝纤维化状态下肝脏纤维化基因的作用(αSMA mRNA表达水平分析)。
具体实施方式
本发明申请人在前期的研究中发现，肝损伤状态下FXR表达水平显著下调，这可能是影响OCA的药理活性的重要因素，在本发明的研究中，提供了维持FXR表达阻断其降解的方案，并发现在维持FXR表达水平的情况下，OCA的药理作用更显著，为肝纤维的治疗提供了更佳的策略。
本发明首先证实，体外培养的肝细胞在损伤状态下FXR蛋白表达水平显著下调。SIRT1激动剂SRT1720可以显著提高FXR的表达水平，抑制其降解。在CCl4诱导的肝纤维化模型中，OCA与SRT1720联用可以显著增强OCA对肝脏FXR信号通路的调控作用，并显著降低血清转氨酶水平，改善肝纤维化状态。综合体内外试验结果，说明本发明的技术方案对肝纤维化的治疗呈现更佳的效果。
下面结合具体实施例，进一步阐述本发明。本发明实施例中所使用的生物材料(实验动物)和试剂，如无特别说明，均可从市售渠道获得。
实施例1 SRT1720可以显著逆转FXR蛋白水平的下调
1实验材料
本发明使用的HepG2细胞系购自上海细胞库；
本发明使用的SRT1720购自MCE公司。
2实验方法
2.1细胞培养
细胞于T25细胞培养瓶(Costar)中生长，放置于37℃，5％CO2且相对湿度为90％的环境中培养。培养基为含10％胎牛血清(FBS)的DMEM培养基中，添加青霉素1unit/ml，以及链霉素1μg/ml。此细胞皆为贴壁细胞，隔天换液，三天分瓶传代。
2.2 Western blot
1)细胞收集后置于冰上，每20μl细胞压积中加入100μl的RIPA细胞裂解液，1％Protease Inhibitor Cocktail(Sigma)，1％磷酸酶抑制剂，充分吹散团块，冰上裂解30min后，超声破碎5次，每次2s，期间暂停数秒以待裂解液冷却。
2)13000g离心10min，所得上层清液为提取到的总蛋白样品，移入新离心管中，使用BCA法测定蛋白含量，加入4×loading buffer，混匀后煮沸10min待上样。
3)制备3％-5％浓缩胶和6％-12％分离胶的SDS-PAGE，电泳分离蛋白样本。将样本充分振匀，每样取50-100μg相同量的总蛋白进行上样。电泳以浓缩胶恒压75V 40min，分离胶恒压115V 60min梯度进行。
4)使用半干转条件进行蛋白转印，将滤纸、切下凝胶和PVDF膜(Bio-Rad)置于半干转缓冲液中平衡，滤纸平放于半干转槽中，上面依次放置PVDF膜，凝胶和另一份滤纸，并小心排净所有层与层间的气泡。将半干转的盖子扣在槽上，设置恒压25V，转印30min。
5)转印后PVDF膜在TBST溶液配制的5％脱脂奶粉封闭液中封闭，于37℃封闭1h。以100μl/cm2PVDF的相对量加入封闭液配制的适量一抗，4℃孵育过夜。
6)用TBST溶液漂洗PVDF膜4次，每次5min。
7)将膜与HRP-结合的二抗稀释液于37℃孵育60min，用TBST溶液漂洗PVDF膜4次，每次5min。
8)使用ChemiDocTM XRS+凝胶成像系统(Bio-Rad)曝光，并用Image Lab TMsoftware进行光密度分析和半定量比较。
3实验结果
3.1在TNFα诱导的HepG2细胞凋亡模型中FXR的表达水平
根据western blot的结果显示(图1)，在TNFα诱导的肝细胞凋亡模型中，随着造模时间的延长，FXR的表达量呈现下降的趋势。
3.2 SIRT1激动剂SRT1720对FXR表达的影响
根据western blot的结果显示(图2)，SIRT1特异性激动剂SRT1720能够显著增加FXR的表达量。
实施例2 SRT1720与OCA联用对肝纤维化的作用
1实验材料
实验小鼠(C57BL/6)购自北京维通利华实验动物技术有限公司；
CCl4购自上海凌峰化学试剂公司，矿物油购置Sigma-Aldrich公司，TrizolRNAiso plus购自Takara公司，逆转录试剂盒和SYBR Green购自Applied Biosystems公司，所用引物由Life公司合成。
其余生物材料/试剂均可从市售途径获得。
其余实验材料同实施例1。
2实验方法
2.1 SRT1720与OCA联用对CCl4诱导的小鼠肝纤维化的作用。
实验前C57BL/6小鼠适应性饲养一周，室温22～26℃，相对湿度40％～60％，明暗交替12h。所有小鼠分笼饲养，自由饮水采食，体重维持在20-22g。本实验分为空白对照组、模型组、SRT1720给药组、OCA给药组和SRT1720联合OCA给药组。SRT1720给药组和联合给药组C57BL/6小鼠进行预给药处理，腹腔注射10mg/kg/day SRT1720，其余组别给予相同剂量的生理盐水。3天后进行CCl4造模，空白对照组给予相同剂量的矿物质油。造模24h后，给药组小鼠给予相应药物处理，其中OCA给药剂量为5mg/kg/day，灌胃。48h后安乐处死小鼠。收集小鼠血液和肝脏。
2.2 Western blot分析
实验方法同实施例1。
2.3 RT-PCR
2.3.1动物组织样本总RNA提取
1)分别称取各小鼠的肝组织样本20mg，加入1.0ml的RNAiso Plus，经均质器匀浆，将匀浆液转移至离心管中，室温静置5min，于4℃，12000g离心5min。
2)转上清800μl，并加入160μl氯仿，剧烈振荡15sec，室温放置5min后12 000g离心15min。样品分为三层：底层为黄色有机相，上层为无色水相和一个中间层。
3)小心转移上层水相300μl到新管中，并加入300μl异丙醇，颠倒混匀后，室温放置10min，而后12000g离心10min，弃去上清；
4)用预冷的75％乙醇1.0ml洗涤RNA沉淀，而后12000g离心5min，弃上清得到总RNA，并用20μl DEPC水复溶，定量后稀释至0.5μg/μl。
2.3.2逆转录
按照说明书要求的体系配比将RNA溶液和试剂盒成分配制成总体积为20μl的体系并设定程序温度进行逆转录，具体配比要求如下：
2.3.3 PCR
PCR体系如下：
PCR使用条件如下：
Stage 1：预变性95℃1min
Stage 2：PCR反应95℃15sec；如60℃30sec for 40Cycles；72℃30sec
Stage 3：融解曲线分析65-95℃，0.5℃/5
3实验结果
3.1 SRT1720与OCA联用对小鼠肝脏FXR蛋白水平的作用
根据western blot结果显示(图3)，经CCl4造模的小鼠肝组织中FXR表达量较正常组明显下降。在CCl4诱导小鼠急性肝损伤模型中，FXR激动剂OCA无法提高FXR的表达量，而SIRT1激动剂SRT1720与OCA联用组FXR表达量显著升高。
3.2 SRT1720与OCA联用对小鼠肝脏FXR信号通路的作用
根据实时RT-PCR的结果显示(图4)，在CCl4诱导小鼠急性肝损伤模型中，Fxr mRNA水平明显下降(P<0.001)，FXR激动剂OCA，SIRT1激动剂SRT1720及二者联用均无法扭转FxrmRNA的水平。但是，FXR激动剂OCA与SIRT1激动剂SRT1720联用显著的提高FXR下游靶基因Shp的mRNA水平，与造模组相比P<0.05，与FXR激动剂OCA给药组相比P<0.01，与SIRT1激动剂SRT1720给药组相比P<0.01。
3.3 SRT1720与OCA联用对小鼠纤维化的改善作用
根据实时RT-PCR的结果显示(图5)，在CCl4诱导小鼠急性肝损伤模型中，肝脏纤维化基因α-SMA mRNA水平显著升高(P<0.001)，FXR激动剂OCA，SIRT1激动剂SRT1720均无法降低α-SMA mRNA的水平。但是，FXR激动剂OCA与SIRT1激动剂SRT1720联用显著的降低了α-SMAmRNA水平，与造模组相比P<0.001，与FXR激动剂OCA给药组相比P<0.001。
Claims (2)
1.FXR激动剂与SIRT1激动剂联用在制备抗肝纤维化药物中的应用；其中，所述的FXR激动剂为奥贝胆酸，SIRT1激动剂为SRT1720。
2.根据权利要求1所述的应用，其特征在于，所述药物是以FXR激动剂与SIRT1激动剂作为活性成分，加上药学上可接受的辅料所制成的药物。
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