脂肪肝研究新进展:抑制Notch信号通路的NAFLD肝纤维化治疗新策略

2019-08-08 肝胆柳叶刀 健康界

肝胆医生蒋贝格非酒精性脂肪性肝病非酒精性脂肪性肝病(Nonalcoholic Fatty Liver Disease NAFLD)是由单纯性肝脏脂肪变性、非酒精性脂肪肝炎(NASH),最终进展到肝纤维化和肝细胞癌的慢性进展性疾病,肝纤维化和肝癌是导致患者死亡的主要预测指标。随着肥胖发病率的升高,NAFLD的发病率也逐年增加。然而,目前FDA尚未批准过针对NASH的治疗药物。Notch是什么?和

肝胆医生蒋贝格

非酒精性脂肪性肝病

非酒精性脂肪性肝病(Nonalcoholic Fatty Liver Disease NAFLD)是由单纯性肝脏脂肪变性、非酒精性脂肪肝炎(NASH),最终进展到肝纤维化和肝细胞癌的慢性进展性疾病,肝纤维化和肝癌是导致患者死亡的主要预测指标。随着肥胖发病率的升高,NAFLD的发病率也逐年增加。然而,目前FDA尚未批准过针对NASH的治疗药物。

Notch是什么?和NAFLD有什么关系?

Notch蛋白是一类在发育过程中与细胞分化相关的受体蛋白家族成员[1],同时也与代谢关系密切。活化的Notch蛋白通过稳定雷帕霉素复合物1(mTORC1),使固醇调节结合蛋白1c(SREBP1c)活性上调,增强肝细胞内甘油三酯的合成[1],从而促进NAFLD的发生发展。

关于Notch和NAFLD肝纤维化的研究最新进展

近期来自美国芝加哥大学的Zhu[2]团队的一项研究报道引起了学者们的广泛关注,NEJM还针对该文发表了一篇clinical implications of basic research的述评。他们的研究显示抑制Notch信号可能是治疗NAFLD肝纤维化的新策略。

在自然条件下,肝细胞分化结束后,Notch信号就失活了,但Zhu团队发现NAFLD患者和饮食诱导的NASH小鼠肝脏中Notch信号通路明显上调,更重要的是,敲除NASH小鼠肝脏的Notch可以使肝纤维化得以显着改善。

既往基于脂肪肝人群的大样本基因多态性的研究都发现,NASH与肝纤维化存在因果关系[3]。Zhu等在啮齿类模型中发现,肝脏特异性敲除Notch的小鼠脂肪肝肝、纤维化程度都明显减轻,而使用缺乏蛋氨酸和胆碱的饮食诱导的非热量、非脂肪依赖性的肝纤维化小鼠中,Notch敲除对肝纤维化进程没有影响。这些数据说明,Notch信号持续激活是NAFLD相关肝纤维化的重要原因,抑制Notch信号能够减轻肝纤维化。

该研究的局限性

当然该研究也不是那么完美,研究中对于Notch信号与肝纤维化密切相关的肝星状细胞活化之间的因果关系并未完全阐明。尽管作者提供了许多数据,说明Spp1蛋白(即骨桥蛋白)表达下调,使肝星状细胞中胶原和组织特异的金属蛋白酶1抑制剂(Timp1)的产生减少,可能与之有关。

尽管如此,抑制Notch信号这一治疗NAFLD的新策略还是非常具有潜力。Zhu的团队还研发出一种Notch蛋白的抑制剂——Nicastrin反义寡核苷酸(减少Notch蛋白的表达),动物实验证实这种抑制剂可以显着减轻饮食诱导的NASH小鼠的肝纤维化程度。

关于Notch和NAFLD肝纤维化的下一步研究方向

肿瘤干细胞是肿瘤的前体,在肿瘤发生、发展和复发过程中扮演十分重要的角色。Notch信号通过促进肿瘤干细胞的发展以及对化疗的抵抗来增强肿瘤的恶性行为。抑制Notch信号是否能够改善肝纤维化相关肝癌患者的预后?是否能够抑制肝癌的复发?这些都是非常值得关注的话题。

另外,还应关注NAFLD的遗传易感性。某些自然发生的SNP多态性能够通过不同的机制加重脂肪肝和纤维化。轻度的Notch信号失活是否能减缓某些特殊遗传背景的人群脂NASH和肝纤维化的发生和发展呢?

另一方面要考虑的问题是,长时间Notch的下调可能会影响胆道,Notch信号的活化能够诱导胆管细胞的分化,从而带来治疗风险。或许特异靶向肝细胞的Notch抑制药物,或者间断给药,能够避免这一风险。

小结

总结一下,就是下调Notch信号是治疗NAFLD患者肝纤维化的候选靶标。还需要更多的研究在人体中证实这个假说,以及进一步阐明Notch信号和肝纤维化之间的分子机制。

参考文献

1. Bi P, Kuang S. Notch signaling as a novel regulator of metabolism. Trends Endocrinol Metab 2015; 26: 248-55.

2. Zhu C, Kim K, Wang X, et al. Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Sci Transl Med 2018; 10: eaat0344.

3. Dongiovanni P, Stender S, Pietrelli A, et al. Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver. J Intern Med 2018; 283: 356-70.

4. Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol 2018; 68: 268-79.

5. Zong Y, Stanger BZ. Molecular mechanisms of liver and bile duct development. Wiley Interdiscip Rev Dev Biol 2012; 1: 643-55.

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content=<a href='/topic/show?id=ba951352387' target=_blank style='color:#2F92EE;'>#OTC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13523, encryptionId=ba951352387, topicName=OTC)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b36f8313624, createdName=ymljack, createdTime=Sat Aug 10 10:22:00 CST 2019, time=2019-08-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1539758, encodeId=ef821539e58eb, content=<a href='/topic/show?id=c61a2e315da' target=_blank style='color:#2F92EE;'>#信号通路#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=27315, encryptionId=c61a2e315da, topicName=信号通路)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b12d13147749, createdName=wgx310, createdTime=Sat Aug 10 10:22:00 CST 2019, time=2019-08-10, status=1, ipAttribution=)]
  4. 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channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12978, encryptionId=0c31129e85f, topicName=Notch信号通路)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=3c472859403, createdName=gracezdd, createdTime=Sat Aug 10 10:22:00 CST 2019, time=2019-08-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1478438, encodeId=39cd14e843880, content=<a href='/topic/show?id=d1a55858e70' target=_blank style='color:#2F92EE;'>#新策略#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58587, encryptionId=d1a55858e70, topicName=新策略)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=da0f7431516, createdName=12498568m52暂无昵称, createdTime=Sat Aug 10 10:22:00 CST 2019, time=2019-08-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1487481, encodeId=4b80148e481ea, 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time=2019-08-10, status=1, ipAttribution=)]
  5. 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channel=null, level=null, likeNumber=43, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12978, encryptionId=0c31129e85f, topicName=Notch信号通路)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=3c472859403, createdName=gracezdd, createdTime=Sat Aug 10 10:22:00 CST 2019, time=2019-08-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1478438, encodeId=39cd14e843880, content=<a href='/topic/show?id=d1a55858e70' target=_blank style='color:#2F92EE;'>#新策略#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=58587, encryptionId=d1a55858e70, topicName=新策略)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=da0f7431516, createdName=12498568m52暂无昵称, createdTime=Sat Aug 10 10:22:00 CST 2019, time=2019-08-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1487481, encodeId=4b80148e481ea, content=<a href='/topic/show?id=ba951352387' target=_blank style='color:#2F92EE;'>#OTC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=13523, encryptionId=ba951352387, topicName=OTC)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b36f8313624, createdName=ymljack, createdTime=Sat Aug 10 10:22:00 CST 2019, time=2019-08-10, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1539758, encodeId=ef821539e58eb, content=<a href='/topic/show?id=c61a2e315da' target=_blank style='color:#2F92EE;'>#信号通路#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=27315, encryptionId=c61a2e315da, topicName=信号通路)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b12d13147749, createdName=wgx310, createdTime=Sat Aug 10 10:22:00 CST 2019, time=2019-08-10, status=1, ipAttribution=)]
    2019-08-10 karmond
  6. 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time=2019-08-10, status=1, ipAttribution=)]
  7. 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  8. 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    2019-08-10 ymljack
  9. 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