Loss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells

BACKGROUND: The liver X receptors (LXRs; α/β) are nuclear receptors known to regulate cholesterol homeostasis and the production of select hematopoietic populations. The objective of this study was to determine the importance of LXRs and a high‐fat high‐cholesterol diet on global hematopoiesis, with special emphasis on endothelial progenitor cells (EPCs), a vasoreparative cell type that is derived from bone marrow hematopoietic stem cells. METHODS AND RESULTS: Wild‐type and LXR double‐knockout (Lxrαβ(−/−)) mice were fed a Western diet (WD) to increase plasma cholesterol levels. In WD‐fed Lxrαβ(−/−) mice, flow cytometry and complete blood cell counts revealed that hematopoietic stem cells, a myeloid progenitor, and mature circulating myeloid cells were increased; EPC numbers were significantly decreased. Hematopoietic stem cells from WD‐fed Lxrαβ(−/−) mice showed increased cholesterol content, along with increased myeloid colony formation compared with chow‐fed mice. In contrast, EPCs from WD‐fed Lxrαβ(−/−) mice also demonstrated increased cellular cholesterol content that was associated with greater expression of the endothelial lineage markers Cd144 and Vegfr2, suggesting accelerated differentiation of the EPCs. Treatment of human umbilical vein endothelial cells with conditioned medium collected from these EPCs increased THP‐1 monocyte adhesion. Increased monocyte adhesion to conditioned medium–treated endothelial cells was recapitulated with conditioned medium from Lxrαβ(−/−) EPCs treated with cholesterol ex vivo, suggesting cholesterol is the main component of the WD inducing EPC dysfunction. CONCLUSIONS: LXRs are crucial for maintaining the balance of hematopoietic cells in a hypercholesterolemic environment and for mitigating the negative effects of cholesterol on EPC differentiation/secretome changes that promote monocyte‐endothelial adhesion.