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Regulation of ACAT, an enzyme involved in cholesterol esterification and foam cell formation in vascular walls

ACAT（一种参与血管壁胆固醇酯化和泡沫细胞形成的酶）的调节

基本信息

批准号：
10671077
负责人：
MIYAZAKI Akira
金额：
$ 2.05万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671077/
关键词：
ACAT macrophage cholesteryl ester vesicle vitamin D differentiation

项目摘要

Acyl-coenzyme A cholesterol acyltransferase (ACAT) catalyzes conversion of free cholesterol to cholesteryl ester inside the cells and plays a key role in formation of macrophage-derived foam cells in atherosclerotic lesions. There are two isoforms of ACAT, ACAT-1 and ACAT-2. Using a specific antibody to human ACAT-1, we immunohistochemically demonstrated that ACAT-1 is highly expressed in human atherosclerotic lesions, particularly in macrophage-derived foam cells. Western blotting of cultured human monocyte-macrophages showed that ACAT-1 protein increases during differentiation of monocytes into macrophages. To identify the factors involved in ACAT-1 induction during monocyte-macrophage differentiation, we tested some candidates with THP-1 cells as a model of human monocytes. WhenTHP-1 cells were treated with a physiological concentration of 1,25-dihydroxyvitamin D3, a factor known to stimulate monocytic differentiation, ACAT-1 was substantially induced suggesting that 1,25-dihydroxyvitamin D3 is involved in ACAT-1 induction during monocytic differentiation.Immunohistochemical analysis of human tissues showed that ACAT-1 is highly expressed in macrophages and their related cells such as alveolar macrophages, Kupffer cells and Langerhans cells in the skin. Steroid hormone-producing cells such as adrenocortical cells, granulosa cells and Leydig cells also showed abundant expression of ACAT-1. Immunoelectronmicroscopic observation revealed that ACAT-1 is located in rough endoplasmic reticulum in human macrophages. However, when cells were convened to foam cells with acetylated LDL, ACAT-1 is more diffusely distributed inside the cells forming small vesicles. These vesicles may play some roles in cholesterol esterification by ACAT-1.

酰基辅酶A胆固醇酰基转移酶(ACAT)催化细胞内游离胆固醇转化为胆固醇酯，在动脉粥样硬化病变中巨噬细胞源性泡沫细胞的形成中起关键作用。ACAT有两种亚型，即ACAT-1和ACAT-2。利用人类ACAT-1的特异性抗体，我们用免疫组织化学方法证明了ACAT-1在人类动脉粥样硬化病变中高表达，特别是在巨噬细胞来源的泡沫细胞中。培养的人单核巨噬细胞的Western blotting显示，在单核细胞向巨噬细胞分化的过程中，ACAT-1蛋白表达增加。为了确定ACAT-1在单核-巨噬细胞分化过程中的诱导因素，我们用THP-1细胞作为人单核细胞的模型对一些候选细胞进行了测试。当生理浓度的1，25-二羟基维生素D3处理THP-1细胞时，ACAT-1被大量诱导，这表明1，25-二羟基维生素D3参与了单核细胞分化过程中ACAT-1的诱导。对人体组织的免疫组织化学分析表明，ACAT-1在皮肤的巨噬细胞及其相关细胞如肺泡巨噬细胞、枯否细胞和朗格汉斯细胞中高表达。肾上腺皮质细胞、颗粒细胞和间质细胞等类固醇激素分泌细胞也大量表达ACAT-1。免疫电子显微镜观察表明，ACAT-1位于人巨噬细胞的粗面内质网中。然而，当细胞被聚集成含有乙酰化低密度脂蛋白的泡沫细胞时，ACAT-1在形成小泡的细胞内分布得更分散。这些小泡可能在ACAT-1的胆固醇酯化反应中起一定作用。