Cell Discovery:上海交大贺明团队揭示酒精性肝病新机制及治疗新靶点​

2021-10-20 “生物世界”公众号 “生物世界”公众号

近日,上海交通大学医学院病理生理学系、细胞分化与凋亡教育部重点实验室贺明教授团队在 Cell Discovery 期刊在线发表了题为:SIRT2-mediated deacetylation and

近年来随着经济发展和生活方式的改变,我国及全球其他国家的酒精性肝病(alcoholic liver disease, ALD)发病率逐年递增,由ALD引发的肝纤维化和肝癌也大大增加。而现在酒精性肝病最主要的防治手段是戒酒,但即便是完全戒酒,也仅有27%患者肝脏功能可以完全恢复正常,其余患者最终会发展为慢性肝炎和肝硬化。由于ALD发病机制复杂,所以仍然没有针对性的药物治疗。

近日,上海交通大学医学院病理生理学系、细胞分化与凋亡教育部重点实验室贺明教授团队在 Cell Discovery 期刊在线发表了题为:SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury 的研究论文。

该研究通过临床资料分析、肝脏基因特异性敲除小鼠模型构建、小鼠基因治疗及细胞分子生物学研究,首次发现肝细胞SIRT2可以对C/EBPβ去乙酰化,并抑制其泛素化降解,进而上调下游靶基因LCN2,减轻酒精引起的脂质过氧化和肝细胞凋亡。该项研究为酒精性肝病(ALD)的防治提供了新的治疗靶点和策略。

Sirtuin 2(SIRT2)是沉默信息调节因子(sirtuin)蛋白家族成员,是在肝脏中高表达的一类NAD+依赖的去乙酰化酶,可通过对不同的底物去乙酰化,参与衰老、应激反应、糖脂代谢、炎症反应等多种生物学功能的调节。

贺明教授课题组长期聚焦蛋白质乙酰化修饰与衰老及肝脏代谢相关疾病方面的研究,在2020年3月作为第一作者在 Cell Metabolism 报道了SIRT2可以通过去乙酰化作用抑制NLRP3炎症小体的组装和活化,进而减轻衰老或高脂饮食引起的慢性炎症和胰岛素抵抗,提示SIRT2在衰老及代谢疾病中发挥重要的调控开关作用。但SIRT2在ALD中的功能尚不清楚。

该研究从临床分析入手,发现ALD病人肝脏样本中SIRT2蛋白表达与ALD严重程度呈明显负相关。进一步利用肝脏SIRT2特异性敲除小鼠发现,肝脏SIRT2特异性缺失加重酒精引起的肝脏脂质沉积、脂质过氧化和肝细胞凋亡。而利用AAV8在肝细胞中特异性过表达SIRT2可以完全抑制酒精引起的肝损伤。

机制方面,首先利用RNAseq发现,SIRT2敲除可以明显抑制酒精引起的急性期反应蛋白的增加,而体内外实验均证实,肝细胞急性期反应蛋白LCN2(lipocaline-2)可以明显抑制ALD,且介导了SIRT2对ALD的保护作用。

通过生物信息学分析和ChIP实验发现SIRT2主要通过C/EBPβ(CCAAT/enhancer-binding protein beta)上调LCN2的转录表达。而肝细胞中的SIRT2通过与C/EBPβ蛋白相互结合,并对K102和K211去乙酰化抑制C/EBPβ泛素化降解,增加其蛋白稳定性,促进其下游靶基因LCN2的转录。

而且更为重要的是,在动物水平,相较于野生型的C/EBPβ,去乙酰化的C/EBPβ突变体可以逆转SIRT2敲除加重的酒精性肝损伤。与机制研究结果一致,临床ALD患者肝脏样本中SIRT2-C/EBPβ-LCN2轴表达呈正相关,且与肝损伤程度呈明显负相关。

总之,该研究发现了ALD发生中肝脏自我保护的新机制,SIRT2-C/EBPβ-LCN2轴可能成为ALD的治疗的新靶点。

上海交通大学基础医学院贺明教授和赵倩教授为共同通讯作者,课题组硕士生张颖婷、阮昕,右江民族医学院龙喜带教授为本论文共同第一作者。研究工作得到了上海交通大学医学院陈国强院士、刘俊岭教授、钟清教授、沈少明研究员、夏立副教授的帮助和支持。该研究得到了国家自然科学基金面上项目、重大研究计划培育项目、上海市自然科学金、浦江人才计划等课题的资助。

原始出处:

Zhang, Y., Long, X., Ruan, X. et al. SIRT2-mediated deacetylation and deubiquitination of C/EBPβ prevents ethanol-induced liver injury. Cell Discov 7, 93 (2021). https://doi.org/10.1038/s41421-021-00326-6.

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    2022-03-06 维他命
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    2022-02-11 yahu
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  4. 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  5. 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  6. 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2021, time=2021-10-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1587924, encodeId=92d9158e92450, content=<a href='/topic/show?id=cb1e1006ebd' target=_blank style='color:#2F92EE;'>#ISC#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10067, encryptionId=cb1e1006ebd, topicName=ISC)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=173417575755, createdName=yankaienglish, createdTime=Fri Oct 22 09:23:52 CST 2021, time=2021-10-22, status=1, ipAttribution=)]
    2021-10-22 lsndxfj
  7. 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  8. 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  9. 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