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Journal of Hepatology:喝酒也可以不伤肝?中国科学家发现酒精伤肝机制,去除这个分子可抵御伤害

2018-03-18 吴非 环球科学ScientificAmeric

在一篇于近期发表于国际著名肝脏学杂志《肝脏病学杂志》的文章中,来自复旦大学的科学家发现,“分选连接蛋白10”(SNX10)的缺失可以抵御酒精性肝损伤。这一发现为减轻酒精过量引起的肝损伤提供了新思路,或将为靶向治疗酒精性肝损伤的药物的诞生指明方向。

春节假期刚刚结束,和亲朋好友团聚时,除了摄入太多大鱼大肉,你是不是也喝了很多酒?

喝酒伤肝已经成为众人皆知的事实。大量过往研究告诉我们,长期大量饮酒可以导致从脂肪变性、酒精性肝炎、脂肪肝到肝癌等多种肝脏损伤。在全球范围内,酒精性肝损伤已经成为一项不容忽视的致死因素。根据世卫组织于2014年发布的《酒精与健康全球状况报告》,饮酒导致超过300万人死亡,占全世界总死亡人数的5.9%。在我国,随着近20多年来人们生活方式的改变,加之过半的中国人存在酒精代谢酶缺陷,酒精性肝病的发病率也在逐年攀升。

酒精主要通过两条途径损伤肝脏:干扰肝脏正常的脂质代谢,使得过量甘油三酯在肝脏中堆积;此外,酒精的摄入导致氧化应激,继而造成肝脏细胞凋亡及炎症。但在过去30多年间,对于酒精性肝病的治疗手段却长期停滞不前。其中的重要原因,细胞抵御酒精损伤的分子机制始终难以破解,因此缺乏靶向控制药物。

在此前的研究中,一种由分子伴侣介导的自噬(chaperone-mediated autophagy,CMA)过程引起了人们的注意。CMA对维持细胞内部环境的稳定起到重要作用,CMA障碍被认为可能是肝脏代谢失调的重要诱因。如能保证CMA过程的正常进行,将有可能为缓解酒精性肝损伤打开新思路。

在近期发表于国际著名肝脏学杂志《肝脏病学杂志》(Journal of Hepatology)的一篇论文中,复旦大学沈晓燕教授带领的团队在这一问题上实现重要突破。

研究团队将目标锁定在一种名为“分选连接蛋白10”(SNX10)的蛋白分子上。研究团队分别选用敲除了SNX10的小鼠,以及正常的野生型小鼠进行对照实验。为了验证SNX10对肝脏代谢的影响,他们用含酒精的液体饲料分别喂养两组小鼠。4周后,研究人员发现对照组小鼠的体重出现明显下降,而敲除了SNX10的小鼠体重保持稳定;相比于野生型小鼠,敲除了SNX10的小鼠血清、肝脏内的甘油三酯、胆固醇浓度明显更低。这些结果共同证实了,SNX10确实是酒精导致脂质代谢失调过程中的重要一环。



在用含酒精饲料喂养后,野生型小鼠(红色)与敲除SNX10的小鼠(蓝色)的体重变化图。

对氧化应激及炎症指标的检测也表明,SNX10的敲除显着减轻了酒精过量引起的肝脏氧化应激和炎症。



含酒精的饮食使对照组小鼠的丙二醛(氧化应激指标)浓度上升(右侧白色),而实验组小鼠的丙二醛含量基本不变(右侧黑色)。

由此可见,SNX10分子的缺失对小鼠肝脏起到全方位的保护作用,那么SNX10是通过什么机制影响肝脏健康的?

沈晓燕团队通过进一步研究找到了答案。文章开头提到,CMA是保证肝脏正常代谢的重要因素,而自噬发生的场所正是溶酶体。当溶酶体大量降解,肝脏代谢自然也受到影响。研究人员发现,在敲除SNX10的小鼠体内,细胞溶酶体LAMP-2A的浓度明显高于对照组,这是因为SNX10的敲除抑制了组织蛋白酶A的活性,从而抑制了溶酶体LAMP-2A的降解、促进CMA过程。


两组小鼠溶酶体LAMP-2A含量的变化曲线。

这项研究的重要意义在于,它首次揭示了SNX10在酒精性肝损伤中的作用,并且可能为靶向治疗酒精性肝损伤的药物的诞生指明了方向。

但必须要指出的是,目前我们距离该类药物的真正问世依旧很遥远。即使酒精性肝损伤能够在将来得到有效的治疗,这并不意味着大家可以放宽心大量饮酒——酒精对人体的危害可不只是对肝脏的损伤。此前的研究已经发现,酒精还会对干细胞造成不可逆损伤,增加患多种癌症的风险;最近的《柳叶刀》子刊也将饮酒与痴呆症联系在一起,并认为饮酒是导致痴呆症的最重要因素。因此,今后再上酒桌时,还是要好好斟酌一番。

原始出处:

YanYou,Wan-Zhen Li, Sulin Zhang,et al.SNX10 mediates alcohol-induced liver injury and steatosis via regulating chaperone-mediated autophagy activation. Journal of Hepatology, Available online 13 February 2018.

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    2018-03-21 changjiu

    学习一下谢谢

    0

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    2018-03-19 gwc384
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encodeId=192429e3394a, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=107, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfDEeydJz0GlP8O0ngrUX6AYCXFic0XDOOAyeQicIqnOd4TrWSwiagJrsFNYuWC1Uc6iavbS1hWt9xtZAhAqLGHqZyl/0, createdBy=42891977006, createdName=1e17414fm02(暂无匿称), createdTime=Sun Mar 18 08:20:46 CST 2018, time=2018-03-18, status=1, ipAttribution=)]
    2018-03-19 ymljack
  7. 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objectType=article, channel=null, level=null, likeNumber=98, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Sun Mar 18 10:14:35 CST 2018, time=2018-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=297365, encodeId=be4329e36541, content=学习了.获益匪浅.感谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=97, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2018/02/27/c53a212859edcad4f60a54feffff50bb.jpg, createdBy=67cf1525321, createdName=13718711b3m, createdTime=Sun Mar 18 09:24:21 CST 2018, time=2018-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=297339, encodeId=192429e3394a, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=107, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfDEeydJz0GlP8O0ngrUX6AYCXFic0XDOOAyeQicIqnOd4TrWSwiagJrsFNYuWC1Uc6iavbS1hWt9xtZAhAqLGHqZyl/0, createdBy=42891977006, createdName=1e17414fm02(暂无匿称), createdTime=Sun Mar 18 08:20:46 CST 2018, time=2018-03-18, status=1, ipAttribution=)]
    2018-03-18 changjiu

    学习一下谢谢

    0

  8. 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objectType=article, channel=null, level=null, likeNumber=98, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Sun Mar 18 10:14:35 CST 2018, time=2018-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=297365, encodeId=be4329e36541, content=学习了.获益匪浅.感谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=97, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2018/02/27/c53a212859edcad4f60a54feffff50bb.jpg, createdBy=67cf1525321, createdName=13718711b3m, createdTime=Sun Mar 18 09:24:21 CST 2018, time=2018-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=297339, encodeId=192429e3394a, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=107, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfDEeydJz0GlP8O0ngrUX6AYCXFic0XDOOAyeQicIqnOd4TrWSwiagJrsFNYuWC1Uc6iavbS1hWt9xtZAhAqLGHqZyl/0, createdBy=42891977006, createdName=1e17414fm02(暂无匿称), createdTime=Sun Mar 18 08:20:46 CST 2018, time=2018-03-18, status=1, ipAttribution=)]
    2018-03-18 龙胆草

    学习谢谢分享

    0

  9. 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objectType=article, channel=null, level=null, likeNumber=98, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4Nd44v3xHnnictn9UpctwtH62EPQ59TMdI9lnqHMgQ16nH7GmGCfpzicsHgjibYVk6vwSpXrC86gMibRkoaIzf5HwSz7/0, createdBy=78cc1691107, createdName=龙胆草, createdTime=Sun Mar 18 10:14:35 CST 2018, time=2018-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=297365, encodeId=be4329e36541, content=学习了.获益匪浅.感谢分享, beContent=null, objectType=article, channel=null, level=null, likeNumber=97, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://cdnapi.center.medsci.cn/medsci/head/2018/02/27/c53a212859edcad4f60a54feffff50bb.jpg, createdBy=67cf1525321, createdName=13718711b3m, createdTime=Sun Mar 18 09:24:21 CST 2018, time=2018-03-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=297339, encodeId=192429e3394a, content=学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=107, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfDEeydJz0GlP8O0ngrUX6AYCXFic0XDOOAyeQicIqnOd4TrWSwiagJrsFNYuWC1Uc6iavbS1hWt9xtZAhAqLGHqZyl/0, createdBy=42891977006, createdName=1e17414fm02(暂无匿称), createdTime=Sun Mar 18 08:20:46 CST 2018, time=2018-03-18, status=1, ipAttribution=)]
    2018-03-18 13718711b3m

    学习了.获益匪浅.感谢分享

    0

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