Abstract
Lipoproteins play a key role in transport of cholesterol to and from tissues. Recent studies have also demonstrated that red blood cells (RBCs), which carry large quantities of free cholesterol in their membrane, play an important role in reverse cholesterol transport. However, the exact role of RBCs in systemic cholesterol metabolism is poorly understood. RBCs were incubated with autologous plasma or isolated lipoproteins resulting in a significant net amount of cholesterol moved from RBCs to HDL, while cholesterol from LDL moved in the opposite direction. Furthermore, the bi-directional cholesterol transport between RBCs and plasma lipoproteins was saturable and temperature-, energy-, and time-dependent, consistent with an active process. We did not find LDLR, ABCG1, or scavenger receptor class B type 1 in RBCs but found a substantial amount of ABCA1 mRNA and protein. However, specific cholesterol efflux from RBCs to isolated apoA-I was negligible, and ABCA1 silencing with siRNA or inhibition with vanadate and Probucol did not inhibit the efflux to apoA-I, HDL, or plasma. Cholesterol efflux from and cholesterol uptake by RBCs from Abca1+/+ and Abca1-/- mice were similar, arguing against the role of ABCA1 in cholesterol flux between RBCs and lipoproteins. Bioinformatics analysis identified ABCA7, ABCG5, lipoprotein lipase, and mitochondrial translocator protein as possible candidates that may mediate the cholesterol flux. Together, these results suggest that RBCs actively participate in cholesterol transport in the blood, but the role of cholesterol transporters in RBCs remains uncertain.
Highlights
Supplementary key words adenosine 5′-triphosphate binding cassette transporter A1 apolipoprotein A-I cholesterol/metabolism cholesterol flux erythrocyte high density lipoprotein low density lipoprotein lipidomics
whole blood (WB) or mixtures of Red blood cells (RBCs) with plasma were incubated at 37°C for 4–24 h, and the cholesterol level in serum or plasma was measured after separating them from cells
Removal of cholesterol from cells occurs via reverse cholesterol transport, where free cholesterol (FC) is transferred from cells to apoA-I-containing lipoproteins and is esterified and transported to liver or intestine for excretion
Summary
Existence of what has been termed a “residual risk” strongly suggests that other players that modulate systemic cholesterol metabolism may contribute to cardiovascular disease risk [1]. Systemic lipoprotein metabolism has been thoroughly investigated, with most findings derived from studies using blood plasma, ignoring a possible contribution of blood cells. Red blood cells (RBCs) occupy almost half of the total blood volume and carry large quantities of free (unesterified) cholesterol in their plasma membrane. This cholesterol can be transferred to or from lipoproteins through nonspecific exchange or by active transport.
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