ATP binding cassette transporter ABCA1 modulates the secretion of apolipoprotein E from human monocyte‐derived macrophages

Background: VLDLR and apoER2 are receptors for reelin and apoE. Results: Reelin or apoE3 induced macrophage ABCA1 expression and increased cholesterol efflux. Down-regulation of VLDLR, apoER2, or inhibition of Dab1, PI3K, PKC and Sp1 attenuated reelin-or apoE3-induced ABCA1 expression. Conclusion: Activation of VLDLR-and apoER2-mediated signaling up-regulates ABCA1 expression. Significance: Up-regulation of ABCA1 expression is a novel function of VLDLR and apoER2.

“…One of them is to induce the expression of apoE (38). Data from this report clearly demonstrated that apoE increases ABCA1 expression via a mechanism involving VLDLR/apoER2.…”

Section: Discussionmentioning

confidence: 59%

Up-regulation of ATP Binding Cassette Transporter A1 Expression by Very Low Density Lipoprotein Receptor and Apolipoprotein E Receptor 2

Chen

Guo

Okoro

et al. 2012

“…Reconstituting these cells with ECM prompted a dramatic increase in cholesterol efflux to apoA-I. The reconstituted efflux was sensitive to glyburide, an inhibitor of ABCA1 function (57)(58)(59)(60), suggesting that the ECM binding to apoA-I and ABCA1 activity function together to promote lipid efflux to apoA-I. In a similar manner, U937 macrophages, which express ABCA1 and lack an active ECM binding site, do not efflux cholesterol to apoA-I (Fig.…”

Section: Discussionmentioning

confidence: 85%

Trypsin-sensitive and Lipid-containing Sites of the Macrophage Extracellular Matrix Bind Apolipoprotein A-I and Participate in ABCA1-dependent Cholesterol Efflux

Burgess

Kiss

Zachariah

et al. 2002

A unique property of the extracellular matrix of J774 and THP-1 cells has been identified, which contributes to the ability of these cells to promote cholesterol efflux. We demonstrate high level apolipoprotein (apo) A-I binding to macrophage cells (THP-1 and J774) and to their extracellular matrix (ECM). However, high level apoA-I binding is not observed on fibroblasts, HepG2 cells, or U937 cells (a macrophage cell line that does not efflux cholesterol to apoA-I or bind apoA-I on their respective ECM). Binding to the ECM of THP-1 or J774 macrophages depends on the presence of apoA-I C-terminal helices and is markedly reduced with a mutant lacking residues 187-243 (apoA-I⌬(187-243)), suggesting that the hydrophobic C terminus forms a hydrophobic interaction with the ECM. ApoA-I binding is lost upon trypsin treatment or with Triton X-100, a preparation method that de-lipidates the ECM. However, binding is recovered with re-lipidation, and is preserved with ECM prepared using cytochalasin B, which conserves the endogenous phospholipid levels of the ECM. We also demonstrate that specific cholesterol efflux to apoA-I is much reduced in cells released from their native ECM, but fully restored when ECM-depleted cells are added back to ECM in the presence of apoA-I. The apoA-Imediated efflux is deficient in plated or suspension U937 macrophages, but is restored to high levels when the suspension U937 cells are reconstituted with the ECM of J774 cells. The ECM-dependent activity was much reduced in the presence of glyburide, indicating participation of ABCA1 (ATP-binding cassette transporter 1) in the efflux mechanism. These studies establish a novel binding site for apoA-I on the macrophage ECM that may function together with ABCA1 in promoting cholesterol efflux.

“…5). This may suggest that an increase of the lipid release mediated by endogenous apoE is also mediated by ABCA1 (32).…”

Section: Discussionmentioning

confidence: 99%

Helical Apolipoproteins Stabilize ATP-binding Cassette Transporter A1 by Protecting It from Thiol Protease-mediated Degradation

Arakawa

Yokoyama

2002

187

179

ATP-binding cassette transporter (ABC) A1 was increased by apolipoprotein A-I without an increase of its message in THP-1 cells. The pulse label study demonstrated that apoA-I retarded degradation of ABCA1. Similar changes were demonstrated by apoA-II, but the effect of high density lipoprotein was almost negligible on the basis of equivalent protein concentration. Thiol protease inhibitors (leupeptin and N-acetyl-Leu-Leunorleucinal (ALLN)) increased ABCA1 and slowed its decay in the cells, whereas none of the proteosome-specific inhibitor lactacystin, other protease inhibitors, or the lysosomal inhibitor NH 4 Cl showed such effects. The effects of apoA-I and ALLN were additive for the increase of ABCA1, and the apoA-I-mediated cellular lipid release was enhanced by ALLN. The data suggest that ABCA1 is rapidly degraded by a thiol protease(s) in the cells unless helical apolipoproteins in their lipid-free form stabilize ABCA1 by protecting it from proteasemediated degradation.Helical apolipoproteins such as apoA-I, apoA-II, apoA-IV, and apoE interact with cell surfaces and generate high density lipoprotein (HDL) 1 by removing cellular phospholipid and cholesterol (1-3). The reaction is recognized as one of the major pathways of cellular cholesterol release along with the diffusion-mediated nonspecific cholesterol efflux (4). Fibroblasts from patients with a genetic defect of plasma HDL lack the interaction with apolipoprotein, indicating that this reaction is a main source of plasma HDL (5, 6). This view is supported by the finding that probucol, which markedly reduces plasma HDL, blocks the cell-apolipoprotein interaction (7-9). Mutations were identified in ATP-binding cassette transporter (ABC) A1 with many HDL-deficient families (10 -12), so that this protein is considered as a key for generation of HDL by the apolipoprotein-cell interaction and release of cellular cholesterol by this pathway.Regulation of ABCA1 expression is primarily by cellular cholesterol level through oxysterol as a ligand for the nuclear receptor liver X receptor (LXR) that acts in a heterodimer with retinoid X receptor (RXR) (13-15). The ligands for RXR (such as retinoids) in this receptor system also up-regulate the ABCA1 gene expression (14,15). In certain types of cell such as RAW264, cyclic AMP and its analogues markedly increase the ABCA1 message and protein by an unknown mechanism (16, 17). In THP-1 cells, differentiation by phorbol ester induces an increase in ABCA1 message level (18). ABCA1 was found in early and late endosomes so that the lysosomal pathway was suggested for its degradation (19). More recently, proteolytic degradation was indicated as a factor involved in regulation of the cellular level of ABCA1 (20). EXPERIMENTAL PROCEDURESCell Culture-THP-1 cells were maintained in RPMI 1640 (Iwaki) containing 10% fetal bovine serum (PAA laboratories) in a humidified atmosphere of 5% CO 2 and 95% air. Differentiation of THP-1 monocytes into macrophages was induced by culturing the cells at a density of 3.0 ϫ 106 cells/well ...