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

Abstract

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 (BM) transplantation experiments suggest that the increased lesion size might be caused by ACAT1 deficiency in macrophages. However, BM contains hematopoietic stem cells (HSCs) which 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 BM cells demonstrated that Acat1-/- causes a higher proportion of the stem cell-enriched LSK population (Lin-Sca1+ckit+) 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. Conclusion ACAT1 plays important roles in hematopoiesis in normal mouse and in Apoe-/- mouse during atherosclerosis development.

Myeloid Acyl-CoA:Cholesterol Acyltransferase 1 Deficiency Reduces Lesion Macrophage Content and Suppresses Atherosclerosis Progression

“…We have reported previously (11) that global Acat1 Ϫ/Ϫ increased the proliferation rates of hematopoietic stem cells and altered their composition within the bone marrow, resulting in significantly higher numbers of myeloid cells in their blood. We also found that Acat1 Ϫ/Ϫ increased the expression of interleukin 3 and interleukin 7 receptors in bone marrow cells, enabling these cells to proliferate more rapidly in response to interleukin 3/interleukin 7-mediated signaling (11). These results show that, to monitor the effects of Acat1 Ϫ/Ϫ in monocytes/macrophages during atherosclerosis development, a better Acat1 KO model is needed.…”

“…The Apoe Ϫ/Ϫ mice were as described previously (11). The Apoe Ϫ/Ϫ /Acat1 Ϫ/Ϫ and Apoe Ϫ/Ϫ /Acat1 ϪM/ϪM mice were generated by crossing Acat1 Ϫ/Ϫ mice or Acat1 ϪM/ϪM mice with Apoe Ϫ/Ϫ mice.…”

“…It was not clear whether the effects observed using the Acat1 Ϫ/Ϫ mice were due to lack of ACAT1 in macrophages or in other cell types. We have shown recently that global Acat1 KO also increases proliferation of hematopoietic stem cells within the bone marrow (BM) and causes leukocytosis in mice (11). Increasing the production of myeloid and lymphoid lineages may affect atherosclerosis at various stages.…”

ACAT1/SOAT1 as a Therapeutic Target for Alzheimer's Disease

“…In mouse studies, the Acat1 knockout (KO) mouse lines, which were independently created by Farese and co-workers, and by Ishibashi and co-workers, were employed to study the roles of ACAT1 in atherosclerosis; the results produced from these two laboratories were equivocal [16,17]. A more recent study showed that in mouse, global deletion of the Acat1 gene, including cells in the bone marrow, causes an increase in hematopoietic progenitor cell proliferation and lead to leukocytosis [18]. Leukocytosis may alter atherosclerosis progression.…”

Stem/Progenitor Cells in Vascular Regeneration

“…30 Furthermore, several groups have studied the effects of genes and microenvironment on the functions of proangiogenic or endothelial progenitor cells in vivo and in vitro. 31,32 A variety of studies support the role of proangiogenic cells in endothelial regeneration. However, a golden standard for endothelial progenitor cell isolation, characterization, and functions is needed for future investigation.…”