Hepatology：采用iPS细胞模型揭示丙戊酸诱发肝毒性机理

2015-02-08 李洁尉黄博纯中国科学报

1月20日，国际著名学术期刊Hepatology（《肝脏》）在线发表了中科院广州生物医药与健康研究院刘兴国研究组的最新研究成果“Valproic acid-induced hepatotoxicity in alpers syndrome is associated with mPTP opening dependent apoptotic sensitivity in an iPSC mo

1月20日，国际著名学术期刊Hepatology（《肝脏》）在线发表了中科院广州生物医药与健康研究院刘兴国研究组的最新研究成果“Valproic acid-induced hepatotoxicity in alpers syndrome is associated with mPTP opening dependent apoptotic sensitivity in an iPSC model”。该研究以病人的诱导多能干细胞及分化获得的肝样细胞为模型，阐明了丙戊酸诱发Alpers-Huttenlocher综合征肝毒性的机理，并建立相应的候选药物筛选策略。这是首次利用iPS技术建立遗传特异的毒理学模型。

线粒体相关肝病分遗传原发性和后天继发性两类，是急性肝功能衰竭的最重要原因，至今没有有效的治疗方法。其中，Alpers-Huttenlocher综合征是线粒体特异性DNA聚合酶POLG突变导致的一种严重的遗传性神经代谢疾病，临床常有难治性癫痫等神经疾病症状。丙戊酸是一种广谱抗癫痫的药物，它对治疗癫痫具有良好的效果。但使用丙戊酸对Alpers-Huttenlocher综合征病人进行治疗时，经常会导致病人急性肝衰竭（约1/3的病人服用丙戊酸3个月发生肝衰竭），造成这一临床现象的机制一直未阐明。

刘兴国研究组将iPS技术应用到Alpers-Huttenlocher综合征中，首次实现该病成纤维细胞的重编程，获得了诱导多能干细胞，并进一步分化为肝样细胞。研究人员通过分析肝样细胞的表型和线粒体形态以及功能的变化，发现病人特异来源的肝细胞线粒体存在形态、能量合成、线粒体DNA含量的缺陷，与正常人来源的肝样细胞进行比较，使用丙戊酸处理后，更容易发生凋亡。研究员进一步研究发现，这种凋亡的敏感性是与线粒体通透性孔道mPTP相关，病人细胞mPTP的异常开放频率导致了“超氧炫”现象的发生，并且使用mPTP特异性抑制剂可以减少因丙戊酸导致病人细胞的凋亡。

该研究在细胞水平阐明了丙戊酸诱发Alpers-Huttenlocher综合症肝毒性的机理，也为解决这一临床难题提供了靶点和候选药物筛选策略。此外，该研究首次将iPS技术应用到遗传特异的临床药物毒性中，是这类临床问题的成功范例。本研究得到了中科院、科技部、国家自然科学基金、广东省及广州市的经费支持。

基于诱导多能干细胞的Alpers-Huttenlocher 综合征（AHS）丙戊酸肝毒性机理研究

Alpers-Huttenlocher 综合征（AHS）丙戊酸肝毒性的线粒体机理

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#插入话题

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2015-04-17 yeaweam

#细胞模型#

124 0
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2015-02-16 windmilL1989

已阅

163 0
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2015-02-10 chengjn

#iPS#

66 0
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2015-02-10 gwc384

#EPA#

54 0
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2015-02-10 steven_u5

#丙戊酸#

92 0
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2015-02-10 wmr115

#iPS细胞#

69 0
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2015-02-10 爆笑小医

#肝毒性#

110 0
[GetPortalCommentsPageByObjectIdResponse(id=1805350, encodeId=6d40180535019, content=<a href='/topic/show?id=e078e79331a' target=_blank style='color:#2F92EE;'>#细胞模型#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=124, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77933, encryptionId=e078e79331a, topicName=细胞模型)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=21e5394, createdName=yeaweam, createdTime=Fri Apr 17 19:59:00 CST 2015, time=2015-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=15862, encodeId=17a61586256, content=已阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=163, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c68e1614119, createdName=windmilL1989, createdTime=Mon Feb 16 14:25:00 CST 2015, time=2015-02-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1377719, encodeId=1a0913e771970, content=<a href='/topic/show?id=17b810004ce' target=_blank style='color:#2F92EE;'>#iPS#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10004, encryptionId=17b810004ce, topicName=iPS)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=69cb413, createdName=chengjn, createdTime=Tue Feb 10 10:59:00 CST 2015, time=2015-02-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1426602, encodeId=674014266024c, content=<a href='/topic/show?id=221d685172' target=_blank style='color:#2F92EE;'>#EPA#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=6851, encryptionId=221d685172, topicName=EPA)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=4a9b4077760, createdName=gwc384, createdTime=Tue Feb 10 10:59:00 CST 2015, time=2015-02-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1507577, encodeId=50e2150e5778a, content=<a href='/topic/show?id=adee2090e8b' target=_blank style='color:#2F92EE;'>#丙戊酸#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=92, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=20907, encryptionId=adee2090e8b, topicName=丙戊酸)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=46789929366, createdName=steven_u5, createdTime=Tue Feb 10 10:59:00 CST 2015, time=2015-02-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1527113, encodeId=fc1a152e113b8, content=<a href='/topic/show?id=24d610019a8' target=_blank style='color:#2F92EE;'>#iPS细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10019, encryptionId=24d610019a8, topicName=iPS细胞)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=a27a11802753, createdName=wmr115, createdTime=Tue Feb 10 10:59:00 CST 2015, time=2015-02-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1622690, encodeId=35ba162269067, content=<a href='/topic/show?id=c81d812342e' target=_blank style='color:#2F92EE;'>#肝毒性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=110, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=81234, encryptionId=c81d812342e, topicName=肝毒性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=395f25, createdName=爆笑小医, createdTime=Tue Feb 10 10:59:00 CST 2015, time=2015-02-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=15316, encodeId=81c21531687, content=iPS应用, beContent=null, objectType=article, channel=null, level=null, likeNumber=173, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=115.231.229.**, createdTime=Mon Feb 09 23:09:00 CST 2015, time=2015-02-09, status=1, ipAttribution=)]
2015-02-09 115.231.229.**

iPS应用

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Hepatology：采用iPS细胞模型揭示丙戊酸诱发肝毒性机理

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