Pete Lollar, MD
Dr. Lollar indicated no relevant conflicts of interest.
Yvan-Charvet L, Pagler T, Gautier EL, et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science. 2010;328:1689-1693.
High-density lipoproteins (HDLs) and low-density lipoproteins (LDLs) transport cholesterol in the circulation. HDL-cholesterol and LDL-cholesterol are called “good” and “bad” cholesterol particles, respectively, based on the correlation of their levels with atherosclerotic cardiovascular diseases. The protective function of HDL is due to a pathway termed “reverse cholesterol transport” in which cholesterol is removed from lipid-laden macrophages in atherosclerotic lesions through interaction of the major HDL apolipoproteins, apoA-I and apoA-II, with the ATP-binding cassette transporters ABCA1 and ABCG1. In addition to LDL, leukocytosis and monocytosis are risk factors for the development of atherosclerosis. Now, an association between leukocytosis and HDL function has been identified by Yvan-Charvet et al. in the laboratory of Alan Tall at Columbia University, who report that the proliferation of hematopoietic stem and progenitor cells (HSPCs) and downstream myeloid progenitors in mice is inhibited by an HDL-mediated pathway.
Prior to this study, it was known that abca1-/-abcg1-/- mice have decreased reverse cholesterol transport and develop accelerated atherosclerosis in a susceptible hypercholesterolemic background. Additionally, abca1-/- abcg1-/- mice display leukocytosis and infiltration of various organs by monocyte-derived macrophage foam cells. In the present study, the investigators found that HSPCs, granulocyte-monocyte progenitors (GMPs), and common myeloid progenitors, but not common lymphoid progenitors, were significantly increased in abca1-/-abcg1-/- mice compared with wild-type mice. Addition of HDL to cultured abca1-/-abcg1-/- and wild-type bone marrow (BM) cells led to a decrease in GMPs and the proliferation rates of interleukin-3 (IL-3) and granulocyte macrophage colony-stimulating factor (GM-CSF)-treated BM cells. The authors speculate that the perhaps unexpected suppression of proliferation of myeloid progenitor cells in abca1-/-abcg1-/- BM is due to alternative, non-ABC pathways.
ApoA-I transgenic mice have increased HDL levels and are resistant to atherosclerosis. Transplantation of abca1-/-abcg1-/- BM into apoA-I transgenic mice led to a decrease in proliferation of HSPCs and decrease in spleen size compared with wild-type recipients. Myeloid cell infiltration in the spleen, heart, liver, and intestine was significantly greater in wild-type recipients of abca1-/-abcg1-/- BM compared with recipients expressing the apoA-I transgene. The presence of apoA-I transgene also suppressed the accelerated atherosclerosis in atherogenic diet-fed LDL receptor-deficient ldlr+/– mice who received abca1-/-abcg1-/- BM. Additionally, the extent of atherosclerosis was correlated with the degree of leukocytosis in abca1-/-abcg1-/- BM recipients and leukocytosis was suppressed by the apoA-I transgene.
IL-3 and GM-CSF increased the proliferation of abca1-/-abcg1-/- BM cells and HSPCs, which was associated with downstream signaling through phospho–extracellular signal-regulated kinase (phospho-ERK). Increased phospho-ERK was associated with increased Ras guanosine triphosphatase activity in the plasma membranes of abca1-/-abcg1-/- BM cells, which was reversed by HDL treatment. Additionally, the number of cells expressing the IL-3 receptor β subunit was increased in abca1-/-abcg1-/- BM cells and HSPCs and was reversed in the presence of the apoA-I transgene. Because the IL-3 and GM-CSF receptors share a common β subunit, ABC transporter deficiency evidently leads to a pathway involving an increase in plasma membrane cholesterol, increased expression of the common β subunit, and increased cell proliferation through Ras/ERK signaling in response to IL-3 and GM-CSF.
The results of this study suggest that suppression of myeloid proliferation, leukocytosis, and monocytosis may represent an additional mechanism by which HDL earns its reputation as good cholesterol.
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