From the Division of Endocrinology and Metabolism, Department of Internal Medicine (T.W., M.T., D.Y., A.T., S.T., H.Y., S.N., K.E., S.I.), Jichi Medical University, Shimotsuke, Japan.
Division of Inflammation Research, Center for Molecular Medicine (T.K., M.T.), Jichi Medical University, Shimotsuke, Japan.
Arterioscler Thromb Vasc Biol. 2018 Nov;38(11):2576-2589. doi: 10.1161/ATVBAHA.118.311648.
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 Results- Ldlr-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-α (tumor necrosis factor-α) 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.
目的- ACAT1（酰基辅酶 A 胆固醇酰基转移酶 1）酯化细胞内游离胆固醇，从而将巨噬细胞转化为动脉粥样硬化病变和皮肤黄色瘤中的胆固醇酯负荷泡沫细胞。然而，具有讽刺意味的是，骨髓中 ACAT1 的缺失会导致动脉粥样硬化的加重和高脂血症小鼠严重皮肤黄色瘤的发生。最近，有报道称胆固醇晶体激活 NLRP3（NACHT、LRR[富含亮氨酸重复序列]和 PYD[吡嗪结构域]结构域蛋白 3）炎性小体，从而促进动脉粥样硬化的发展。本研究旨在阐明 NLRP3 炎性小体在 ACAT1 缺乏引起的动脉粥样硬化和皮肤黄色瘤恶化中的作用。
方法和结果- 将 Ldlr-/- 小鼠的骨髓移植到 WT（野生型）小鼠和缺乏 ACAT1、NLRP3 或两者的小鼠中。在 4 种类型的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。移植 Acat1-/-骨髓的小鼠发生严重的皮肤黄色瘤，充满大量巨噬细胞和胆固醇裂隙，炎症细胞因子表达明显增加，并伴有明显的动脉粥样硬化。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。用乙酰化 LDL（低密度脂蛋白）处理后，Acat1-/-腹腔巨噬细胞显示 CHOP（CCAAT/增强子结合蛋白同源蛋白）和 TNF-α（肿瘤坏死因子-α）的表达增强，但没有炎性小体激活的证据。
结论- 骨髓来源细胞中 ACAT1 的缺失加剧了皮肤黄色瘤和动脉粥样硬化。皮肤黄色瘤的发展主要是通过 NLRP3 炎性小体的激活诱导的。
