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

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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.