Acat1 Gene Ablation in Mice Increases Hematopoietic Progenitor Cell Proliferation in Bone Marrow and Causes Leukocytosis

Objective-To investigate the role of acyl-CoA:cholesterol acyltransferase 1 (ACAT1) in hematopoiesis. Approach and Results-ACAT1 converts cellular cholesterol to cholesteryl esters for storage in multiple cell types and is a potential drug target for human diseases. In mouse models for atherosclerosis, global Acat1 knockout causes increased lesion size; bone marrow transplantation experiments suggest that the increased lesion size might be caused by ACAT1 deficiency in macrophages. However, bone marrow contains hematopoietic stem cells that give rise to cells in myeloid and lymphoid lineages; these cell types affect atherosclerosis at various stages. Here, we test the hypothesis that global Acat1(-/-) may affect hematopoiesis, rather than affecting macrophage function only, and show that Acat1(-/-) mice contain significantly higher numbers of myeloid cells and other cells than wild-type mice. Detailed analysis of bone marrow cells demonstrated that Acat1(-/-) causes a higher proportion of the stem cell-enriched Lin(-)Sca-1(+)c-Kit(+) population to proliferate, resulting in higher numbers of myeloid progenitor cells. In addition, we show that Acat1(-/-) causes higher monocytosis in Apoe(-/-) mouse during atherosclerosis development. Conclusions-ACAT1 plays important roles in hematopoiesis in normal mouse and in Apoe(-/-) mouse during atherosclerosis development.