Role of ACAT1-positive late endosomes in macrophages: cholesterol metabolism and therapeutic applications for Niemann-Pick disease type C.
Role of ACAT1-positive late endosomes in macrophages: cholesterol metabolism and therapeutic applications for Niemann-Pick disease type C.
复制标题
DOI：
10.2152/jmi.61.270
复制
发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Naomi Sakashita;Xiao-feng Lei;M. Kamikawa;Kazuchika Nishitsuji
中科院分区：
文献类型：
--
作者：
Naomi Sakashita;Xiao-feng Lei;M. Kamikawa;Kazuchika Nishitsuji
处于高脂状态的巨噬细胞积累胆固醇酯并发育成泡沫转化的巨噬细胞。在这一转变过程中，巨噬细胞表现出内质网的碎裂，从而产生酰基辅酶A：胆固醇酰基转移酶1(ACAT1)阳性的晚期内聚体(ACAT1-LE)。ACAT1-LE阳性的巨噬细胞有效地酯化修饰的或天然的低密度脂蛋白衍生的游离胆固醇，从而导致有效的胆固醇酯化以及动脉粥样硬化斑块的形成。这些巨噬细胞表现出显著的胆固醇酯形成，即使当游离胆固醇从晚期内吞体内排出受到损害时，这表明游离胆固醇在ACAT1-LE被酯化。晚期内体胆固醇外流的遗传阻断会导致C型尼曼-皮克病(NPC)，这是一种遗传性溶酶体蓄积性疾病，伴有进行性神经变性。在具有NPC表型的巨噬细胞中诱导ACAT1-LE可显著恢复胆固醇的酯化。此外，体内ACAT1-LE诱导显著延长了鼻咽癌表型小鼠的寿命。因此，ACAT1-LE不仅能调节细胞内胆固醇代谢，还能改善鼻咽癌的病理生理。
Macrophages in hyperlipidemic conditions accumulate cholesterol esters and develop into foamy transformed macrophages. During this transformation, macrophages demonstrate endoplasmic reticulum fragmentation and consequently produce acyl coenzyme A: cholesterol acyltransferase 1 (ACAT1)-positive late endosomes (ACAT1-LE). ACAT1-LE-positive macrophages effectively esterify modified or native low-density lipoprotein-derived free cholesterol, which results in efficient cholesterol esterification as well as atherosclerotic plaque formation. These macrophages show significant cholesterol ester formation even when free cholesterol egress from late endosomes is impaired, which indicates that free cholesterol is esterified at ACAT1-LE. Genetic blockade of cholesterol egress from late endosomes causes Niemann-Pick disease type C (NPC), an inherited lysosomal storage disease with progressive neurodegeneration. Induction of ACAT1-LE in macrophages with the NPC phenotype led to significant recovery of cholesterol esterification. In addition, in vivo ACAT1-LE induction significantly extended the lifespan of mice with the NPC phenotype. Thus, ACAT1-LE not only regulates intracellular cholesterol metabolism but also ameliorates NPC pathophysiology.