Interaction with proteoglycans enhances the sterol efflux produced by endogenous expression of macrophage apoE

Abstract

Endogenous expression of apolipoprotein (apo)Ein macrophages facilitates cholesterol efflux in the presence and absence of extracellular sterol acceptors. A proteoglycanassociated pool of apoE has also been described. The relationship between a proteoglycan-associated pool of apoE and enhanced cholesterol efflux was investigated in these studies. Inhibition of proteoglycan expression reduced cholesterol efflux from apoE-expressing cells ( J774E ؉ ) in the presence and absence of HDL, but did not do so from nonexpressing cells ( J774E ؊ ). The effect of proteoglycan depletion on sterol efflux from J774E ϩ cells was confirmed by measuring differences in cell sterol mass, secreted sterol mass, and sterol efflux rates. Furthermore, apoE-containing particles secreted from proteoglycan-depleted J774E ؉ cells were denser than those secreted from J774E ؉ cells with intact proteoglycan expression. Also, in J774E ؉ cells with intact proteoglycans, apoE particles isolated from the cell surface proteoglycan layer were denser than secreted particles. The apoE-lipid particles isolated from the cell surface proteoglycan layer had a lower lipid-to-apoE and cholesterol-to-apoE ratio compared with secreted particles. In distinction, proteoglycan depletion of J774E ؊ cells did not reduce sterol efflux produced by the exogenous addition of apoE. These observations indicate that one mechanism by which endogenous expression of apoE facilitates effective cholesterol efflux from macrophages is related to its retention at the cell surface in a proteoglycan-associated pool. Further, our data suggest that apoE arrives at the cell surface in a relatively lipid-poor state, and that a proximate source of lipid available to the proteoglycan-bound apoE at the cell surface resides in the plasma membrane. -Lin, C-Y., Z. H. Huang, and T. Mazzone. Interaction with proteoglycans enhances the sterol efflux produced by endogenous expression of macrophage apoE .

Role of the N- and C-Terminal Domains in Binding of Apolipoprotein E Isoforms to Heparan Sulfate and Dermatan Sulfate: A Surface Plasmon Resonance Study

“…The various anti-atherogenic functions of apoE, such as facilitated remnant lipoprotein uptake by the liver , and cholesterol efflux from macrophages , , are achieved through its interaction with cell-surface GAG. Because receptor−ligand interactions at the cell surface do not occur at equilibrium, it is important to establish the kinetics of apoE−GAG association and dissociation.…”

“…The interaction of apoE with CS and/or DS proteoglycans is responsible for the retention of high-density lipoproteins (HDLs) on the extracellular matrix of arterial smooth muscle cells (14), and the uptake of β-very low density lipoprotein in the brain (15). In addition, apoE-mediated cholesterol efflux from macrophages is modulated by cell-surface proteoglycans (16,17). ApoE contains two independently folded functional domains; these are a 22 kDa N-terminal domain (residues 1-191) and a 10 kDa C-terminal domain (residues 216-299) linked by a hinge region (18,19).…”

“…The interaction of apoE with CS and/or DS proteoglycans is responsible for the retention of high-density lipoproteins (HDLs) on the extracellular matrix of arterial smooth muscle cells , and the uptake of β-very low density lipoprotein in the brain . In addition, apoE-mediated cholesterol efflux from macrophages is modulated by cell-surface proteoglycans , .…”

ApoE-dependent sterol efflux from macrophages is modulated by scavenger receptor class B type I expression

“…We have previously shown that a significant fraction of cellular apoE in macrophages is present on the cell sur-face (17,23), and that this cell surface pool serves as the immediate precursor for secreted apoE (17). We have also shown that apoE in this cell surface pool plays a major role in facilitating the sterol efflux produced by the endogenous expression of apoE in macrophages (24). The cellular apoE measured in Fig.…”

“…However, the increased expression of SR-BI appeared to accelerate the degradation of newly synthesized apoE and, thereby, reduce the amount of apoE secreted from cells. We have previously shown that apoE in a macrophage cell surface pool is important for facilitating the sterol and phospholipid efflux produced by the endogenous expression of apoE (24). We, therefore, believe that the most likely mechanism for the reduced sterol efflux after increased SR-BI expression in apoE-expressing cells is the increased degradation of newly synthesized apoE leading to a reduced cell surface pool of apoE (Fig.…”