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Nature review immunology：胆固醇炎症反应与动脉粥样硬化

2015-01-27 佚名 生物谷

胆固醇动脉粥样硬化
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进入工业化社会以来，人们的饮食发生了很大的改变。长期食用富含脂肪与固醇的食物使血液系统中富含胆固醇的低密度脂蛋白（LDL）含量增高，促进了胆固醇在动脉血管壁上的过量沉积，并且引起炎症反应，最终造成动脉粥样硬化。修饰后LDL作为一类细胞表面TLR的配体，本身可以触发先天性免疫反应，巨噬细胞受到修饰后LDL的刺激后会发生吞噬作用，从而造成了胆固醇在胞内的累积，而这一效应又会增强下一轮的免疫反应。另一方

进入工业化社会以来，人们的饮食发生了很大的改变。长期食用富含脂肪与固醇的食物使血液系统中富含胆固醇的低密度脂蛋白（LDL）含量增高，促进了胆固醇在动脉血管壁上的过量沉积，并且引起炎症反应，最终造成动脉粥样硬化。修饰后LDL作为一类细胞表面TLR的配体，本身可以触发先天性免疫反应，巨噬细胞受到修饰后LDL的刺激后会发生吞噬作用，从而造成了胆固醇在胞内的累积，而这一效应又会增强下一轮的免疫反应。另一方面，高密度脂蛋白（HDL）能够将胆固醇从胞浆内向外运输，这一过程会起到控制免疫反应的效果。以上说明胆固醇在胞浆内的积累能够调控免疫反应。然而这一过程是如何发生的呢？

反向固醇转运（RCT）与炎症反应：胆固醇向胞外的转运依赖于转运蛋白ABCA1与ABCG1，最近研究发现，LPS的刺激能够降低ABCG1与ABCA1的活性，从而降低巨噬细胞清除胆固醇的能力。反过来，肝脏与小肠分泌的HDL能够与LPS结合，从而抑制其产生免疫反应的能力。另外，在急性感染过程中，HDL的正常功能丧失，而且会从抗炎性分子转变为产生促炎性分子。研究发现：在动脉粥样硬化伤口产生的炎性刺激下，巨噬细胞髓过氧化物酶（MPO）活性上升，HDL被其氧化，引起功能丧失；另外，胆固醇转运受体ABCA1也会被MPO氧化，引起胆固醇向外转运能力的下降。
 
胆固醇积累引起的炎症反应机制：许多研究已经证实，被修饰后的LDL可以作为一类配体引起巨噬细胞免疫反应，起作用机理与LPS相同。另外，胆固醇向胞外的转运能够起到抑制免疫反应的作用。反过来说，胆固醇的胞内积累能够起到促进炎症反应的作用。那么这一效应是如何实现的呢？研究发现，缺失了ABCA1与ABCG1的小鼠巨噬细胞内部胆固醇的含量增高，而且在受到TLR刺激之后免疫反应更加强烈，同时在受到修饰后LDL刺激时发生更强的凋亡现象。巨噬细胞特异性ABCA1与ABCG1缺失小鼠产生更加明显的动脉粥样硬化症状，病灶中大量的胆固醇积累引起了胆固醇晶体的形成。研究发现巨噬细胞吞噬胆固醇晶体或胆固醇晶体在巨噬细胞内部形成均会引起炎症小体的激活。由于炎症小体的激活依赖于两步信号：NFkB priming以及inflammasome聚集。前者已经证明是由修饰后LDL刺激TLR产生的，而后者目前被推测为是后胆固醇的晶体引起的。近年来有很多文章揭示胆固醇晶体在炎症小体激活过程中的作用，然而目前还没有明确的结论。
 
炎症反应的负向调节机制：首先，LXR转录因子是抑制胆固醇引起的炎症反应的关键蛋白。它能够促进胆固醇通过ABCA1与ABCG1向胞外转运，同时，LXR能够促进一些调控不饱和脂肪酸合成的基因的表达，这些不饱和脂肪酸能够抑制NF-kB的活性，等等。值得注意的是，胆固醇在巨噬细胞内的积累会反馈抑制其内源性胆固醇的形成。使得大量胆固醇前体物质-链甾醇的胞内积累，它可以调节LXR的表达。以上说明胆固醇同时具有促进炎症反应与抑制炎症反应的作用。最后，在动脉粥样硬化的过程中，胆固醇也会引导大量骨髓细胞的分化与迁移。
 
目前治疗动脉粥样硬化的药物主要是负责降低LDL中胆固醇含量的他汀类药物。然而这类药物具有非常强的副作用。基于以上事实，LXR以及能够提高人体内HDL的含量，或者激活APOA1（一类HDL的转运蛋白）的药物被认为是一类重要的抗动脉粥样硬化的靶点作为相关药物开发的首选。

原始出处

Tall AR1, Yvan-Charvet L2.Cholesterol, inflammation and innate immunity.Nat Rev Immunol. 2015 Jan 23

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  1. [GetPortalCommentsPageByObjectIdResponse(id=75198, encodeId=8aebe5198b2, content=前因后果，还是互为因果，还是缠绵不休！, beContent=null, objectType=article, channel=null, level=null, likeNumber=121, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=225a1697989, createdName=1de7460am01(暂无匿称), createdTime=Fri Apr 01 21:40:00 CST 2016, time=2016-04-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1880471, encodeId=d55218804e101, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Tue Feb 03 16:22:00 CST 2015, time=2015-02-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995804, encodeId=0969199580463, content=<a href='/topic/show?id=a1751540260' target=_blank style='color:#2F92EE;'>#review#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15402, encryptionId=a1751540260, topicName=review)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=30bd35, createdName=xugumin, createdTime=Fri Jul 03 03:22:00 CST 2015, time=2015-07-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1944376, encodeId=07fd19443e622, content=<a href='/topic/show?id=411de6300ad' target=_blank style='color:#2F92EE;'>#粥样硬化#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=76300, encryptionId=411de6300ad, topicName=粥样硬化)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b30d401, createdName=huangshifeng, createdTime=Thu Mar 26 14:22:00 CST 2015, time=2015-03-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=16237, encodeId=db901623e2e, content=已阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=152, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=da6b7222, createdName=chinayinhan, createdTime=Tue Feb 17 01:00:00 CST 2015, time=2015-02-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1320809, encodeId=a35a132080958, content=<a href='/topic/show?id=43de6e0076f' target=_blank style='color:#2F92EE;'>#炎症反应#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=67007, encryptionId=43de6e0076f, topicName=炎症反应)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b73f484, createdName=lsj628, createdTime=Thu Jan 29 00:22:00 CST 2015, time=2015-01-29, status=1, ipAttribution=)]
    2016-04-01 1de7460am01(暂无匿称)

    前因后果，还是互为因果，还是缠绵不休！

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=75198, encodeId=8aebe5198b2, content=前因后果，还是互为因果，还是缠绵不休！, beContent=null, objectType=article, channel=null, level=null, likeNumber=121, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=225a1697989, createdName=1de7460am01(暂无匿称), createdTime=Fri Apr 01 21:40:00 CST 2016, time=2016-04-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1880471, encodeId=d55218804e101, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Tue Feb 03 16:22:00 CST 2015, time=2015-02-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995804, encodeId=0969199580463, content=<a href='/topic/show?id=a1751540260' target=_blank style='color:#2F92EE;'>#review#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15402, encryptionId=a1751540260, topicName=review)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=30bd35, createdName=xugumin, createdTime=Fri Jul 03 03:22:00 CST 2015, time=2015-07-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1944376, encodeId=07fd19443e622, content=<a href='/topic/show?id=411de6300ad' target=_blank style='color:#2F92EE;'>#粥样硬化#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=76300, encryptionId=411de6300ad, topicName=粥样硬化)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b30d401, createdName=huangshifeng, createdTime=Thu Mar 26 14:22:00 CST 2015, time=2015-03-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=16237, encodeId=db901623e2e, content=已阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=152, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=da6b7222, createdName=chinayinhan, createdTime=Tue Feb 17 01:00:00 CST 2015, time=2015-02-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1320809, encodeId=a35a132080958, content=<a href='/topic/show?id=43de6e0076f' target=_blank style='color:#2F92EE;'>#炎症反应#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=67007, encryptionId=43de6e0076f, topicName=炎症反应)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b73f484, createdName=lsj628, createdTime=Thu Jan 29 00:22:00 CST 2015, time=2015-01-29, status=1, ipAttribution=)]
    2015-02-03 liye789132251

    #Nat#

    0

  3. [GetPortalCommentsPageByObjectIdResponse(id=75198, encodeId=8aebe5198b2, content=前因后果，还是互为因果，还是缠绵不休！, beContent=null, objectType=article, channel=null, level=null, likeNumber=121, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=225a1697989, createdName=1de7460am01(暂无匿称), createdTime=Fri Apr 01 21:40:00 CST 2016, time=2016-04-01, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1880471, encodeId=d55218804e101, content=<a href='/topic/show?id=3b2112532d8' target=_blank style='color:#2F92EE;'>#Nat#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=12532, encryptionId=3b2112532d8, topicName=Nat)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e6f107, createdName=liye789132251, createdTime=Tue Feb 03 16:22:00 CST 2015, time=2015-02-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995804, encodeId=0969199580463, content=<a href='/topic/show?id=a1751540260' target=_blank style='color:#2F92EE;'>#review#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=15402, encryptionId=a1751540260, topicName=review)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=30bd35, createdName=xugumin, createdTime=Fri Jul 03 03:22:00 CST 2015, time=2015-07-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1944376, encodeId=07fd19443e622, content=<a href='/topic/show?id=411de6300ad' target=_blank style='color:#2F92EE;'>#粥样硬化#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=76300, encryptionId=411de6300ad, topicName=粥样硬化)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b30d401, createdName=huangshifeng, createdTime=Thu Mar 26 14:22:00 CST 2015, time=2015-03-26, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=16237, encodeId=db901623e2e, content=已阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=152, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=da6b7222, createdName=chinayinhan, createdTime=Tue Feb 17 01:00:00 CST 2015, time=2015-02-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1320809, encodeId=a35a132080958, content=<a href='/topic/show?id=43de6e0076f' target=_blank style='color:#2F92EE;'>#炎症反应#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=27, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=67007, encryptionId=43de6e0076f, topicName=炎症反应)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=b73f484, createdName=lsj628, createdTime=Thu Jan 29 00:22:00 CST 2015, time=2015-01-29, status=1, ipAttribution=)]
    2015-07-03 xugumin

    #review#

    0

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    2015-03-26 huangshifeng

    #粥样硬化#

    0

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    2015-02-17 chinayinhan

    已阅

    0

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    2015-01-29 lsj628

    #炎症反应#

    0

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