Inflammasome Activation Aggravates Cutaneous Xanthomatosis and Atherosclerosis in ACAT1 (Acyl-CoA Cholesterol Acyltransferase 1) Deficiency in Bone Marrow
Inflammasome Activation Aggravates Cutaneous Xanthomatosis and Atherosclerosis in ACAT1 (Acyl-CoA Cholesterol Acyltransferase 1) Deficiency in Bone Marrow
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DOI：
10.1161/atvbaha.118.311648
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发表时间：
2018-11-01
影响因子：
8.7
通讯作者：
Ishibashi, Shun
中科院分区：
文献类型：
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作者：
Wakabayashi, Tetsuji;Takahashi, Manabu;Ishibashi, Shun
目的
酰基辅酶A胆固醇酰基转移酶1（ACAT1）使细胞内游离胆固醇酯化，从而在动脉粥样硬化病变和皮肤黄色瘤中将巨噬细胞转化为富含胆固醇酯的泡沫细胞。然而，矛盾的是，骨髓中ACAT1的缺失会导致高脂血症小鼠动脉粥样硬化加重以及严重皮肤黄色瘤的形成。最近，有报道称胆固醇晶体激活NLRP3（含NACHT、LRR（富含亮氨酸重复序列）和PYD（热蛋白结构域）结构域的蛋白3）炎症小体，从而促进动脉粥样硬化的发展。本研究旨在阐明NLRP3炎症小体在ACAT1缺乏诱导的动脉粥样硬化和皮肤黄色瘤恶化中的作用。
方法与结果
将低密度脂蛋白受体基因敲除（Ldlr - null）小鼠分别移植野生型（WT）小鼠以及缺乏ACAT1、NLRP3或两者均缺乏的小鼠的骨髓。在给这4种小鼠喂食高胆固醇饮食后，我们比较了它们的动脉粥样硬化和皮肤病变情况。移植了Acat1基因缺失骨髓的小鼠出现了严重的皮肤黄色瘤，瘤内充满大量巨噬细胞和胆固醇裂隙，炎症细胞因子表达显著增加，动脉粥样硬化也加重。NLRP3的缺失完全逆转了皮肤黄色瘤，而仅部分改善了动脉粥样硬化。经乙酰化低密度脂蛋白（LDL）处理后，Acat1基因缺失的腹腔巨噬细胞显示CHOP（C/EBP（CCAAT/增强子结合蛋白）同源蛋白）和肿瘤坏死因子 - α（TNF - α）表达增强，但没有炎症小体激活的迹象。
结论
骨髓来源细胞中ACAT1的缺失会加重皮肤黄色瘤和动脉粥样硬化。皮肤黄色瘤的形成主要是通过NLRP3炎症小体激活诱导的。
Objective ACAT1 (Acyl-CoA cholesterol acyltransferase 1) esterifies cellular free cholesterol, thereby converting macrophages to cholesteryl ester-laden foam cells in atherosclerotic lesions and cutaneous xanthoma. Paradoxically, however, loss of ACAT1 in bone marrow causes the aggravation of atherosclerosis and the development of severe cutaneous xanthoma in hyperlipidemic mice. Recently, it has been reported that cholesterol crystals activate NLRP3 (NACHT, LRR [leucine-rich repeats], and PYD [pyrin domain] domain-containing protein 3) inflammasomes, thereby contributing to the development of atherosclerosis. The present study aimed to clarify the role of NLRP3 inflammasomes in the worsening of atherosclerosis and cutaneous xanthoma induced by ACAT1 deficiency.Approach and ResultsLdlr-null mice were transplanted with bone marrow from WT (wild type) mice and mice lacking ACAT1, NLRP3, or both. After the 4 types of mice were fed high-cholesterol diets, we compared their atherosclerosis and skin lesions. The mice transplanted with Acat1-null bone marrow developed severe cutaneous xanthoma, which was filled with numerous macrophages and cholesterol clefts and had markedly increased expression of inflammatory cytokines, and increased atherosclerosis. Loss of NLRP3 completely reversed the cutaneous xanthoma, whereas it improved the atherosclerosis only partially. Acat1-null peritoneal macrophages showed enhanced expression of CHOP (C/EBP [CCAAT/enhancer binding protein] homologous protein) and TNF- (tumor necrosis factor-) but no evidence of inflammasome activation, after treatment with acetylated LDL (low-density lipoprotein).Conclusions Elimination of ACAT1 in bone marrow-derived cells aggravates cutaneous xanthoma and atherosclerosis. The development of cutaneous xanthoma is induced mainly via the NLRP3 inflammasome activation.