. Mechanism of ATP-binding cassette transporter A1-mediated cellular lipid efflux to apolipoprotein A-I and formation of high density lipoprotein particles. J Biol Chem. 2007 Aug 24;282(34):25123-30. PubMed.

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  1. ABCA1 and Lipid Efflux: Easy as 1, 2, 3
    The ATPase-cassette transporter ABCA1 is a key modulator of apolipoprotein E (ApoE) metabolism in the central nervous system. In mice, ABCA1 deficiency leads to a 70 percent loss of ApoE levels in the brain (1,2), and the low level of ApoE that remains in the brain and cerebrospinal fluid of ABCA1-deficient animals is poorly lipidated. Astrocytes and microglia are the primary sources of ApoE in the central nervous system, and glia devoid of ABCA1 exhibit reduced ApoE secretion, are impaired in cholesterol efflux to ApoE, and accumulate lipids under normal culture conditions. Intriguingly, this ABCA1-mediated lipidation of ApoE influences amyloid deposition in vivo. In a series of three back-to-back publications, three independent laboratories crossed ABCA1-deficient mice to a total of four independent murine models of AD to determine the impact of ABCA1 on amyloid burden, Aβ levels, and ApoE levels (3-5). All of these studies, as well as a more recent report, found that elimination of ABCA1 reduced ApoE levels but had no measurable impact on steady-state Aβ levels (3-6). Because ApoE is required for amyloid deposition in mice (7), each group predicted that fewer amyloid plaques would be observed in the absence of ABCA1. However, amyloid burden was not decreased in any of the models examined, and, in direct contrast to expectations, was significantly increased in two of the four models. These observations suggest that ABCA1 affects amyloid deposition or clearance through its effects on ApoE secretion or lipidation. Understanding more about how ABCA1 transfers lipids to apolipoprotein acceptor molecules may lead to ways to modulate ApoE function and slow Aβ deposition or promote Aβ clearance.

    The primary biochemical function of ABCA1 is to catalyze the ATP-dependent transport of cholesterol and phospholipids from the plasma membrane to lipid-free apolipoprotein acceptors. Outside the central nervous system, ApoA-I is the major lipid acceptor for ABCA1. Lipid efflux from ABCA1 to lipid-free ApoA-I is the rate-limiting step in the formation of immature, discoidal, pre-β high density lipoprotein (HDL) particles. In addition to ApoA-I, ABCA1 can also deliver lipids to other apolipoproteins, including ApoE, (8,9) as well as to synthetic amphipathic α-helices. Exactly how ABCA1 transfers lipids to acceptor molecules is a subject of considerable investigation. One model proposes that direct contact between ABCA1 and ApoA-I induces the net transfer of phospholipids and cholesterol (10-13). A second model proposes that ABCA1 translocates lipids to the exofacial leaflet of the plasma membrane independent of ApoA-I, and this generates a membrane microenvironment required for subsequent ApoA-I docking and lipid efflux (14-16). Whether transfer of phospholipids and cholesterol onto ApoA-I and other apolipoproteins occurs simultaneously (17-21) or sequentially (22-25) remains to be fully elucidated. Finally, whether lipid efflux occurs solely at the plasma membrane, or may also involve the internalization and resecretion of apolipoproteins (26), is not yet fully understood.

    Michael Phillips and colleagues now propose a new, three step model of ABCA1-mediated lipid efflux (27). Using J774 macrophages as a model system, Phillips and colleagues propose that lipid-free ApoA-I first makes direct contact with ABCA1 that stabilizes ABCA1 at the cell surface and enhances the movement of phospholipid from the cytofacial leaflet to the exofacial leaflet of the plasma membrane, using the phospholipid translocase activity of ABCA1. The torsional strain produced by this unequal distribution of phospholipids is relieved by forming bulges of plasma membrane that protrude from the cell in specific domains with high curvature. Because ApoA-I binds considerably more avidly to curved membranes than to planar bilayers, these exovasiculated membrane domains serve as sites for high-affinity, high capacity ApoA-I binding. The third and rate-limiting step of this model is the insertion of ApoA-I amphipathic α-helices into these exovasiculated domains, which solubilizes membrane lipids to form a heterogenous mixture of nascent discoidal particles between 9-12 nm in diameter that contain either two or three ApoA-I molecules, phospholipids, and some cholesterol.

    This new model proposed by Phillips and coworkers raises some very intriguing questions about whether ABCA1 may be acting similarly in the central nervous system with respect to ApoE. Unlike ApoE, which is abundantly expressed in brain, ApoA-I is not synthesized within the central nervous system and only very low levels of ApoA-I are taken up from the plasma into the cerebrospinal fluid where it associates with mature spherical lipoprotein particles. Although it is known that ApoE can accept lipids from ABCA1, the Phillips group points out that it will be important to determine not only how ApoE and ApoA-I compare in each of the three steps of this new model, but also whether differences between human ApoE2, ApoE3 and ApoE4 isoforms impact their function in this model system. Additionally, the J774 macrophage cells used by the Phillips group to develop their model relies solely upon exogenous ApoA-I as a lipid acceptor. However, the major sources of HDL in the plasma are hepatocytes and intestinal enterocytes, each of which synthesize and secrete ApoA-I. How endogenously produced apolipoproteins may function with respect to the three-step model of ABCA1 efflux now becomes a central question that is of great importance to glial cells, which secrete ApoE in an ABCA1-dependent manner. Finally, the Phillips three-step model proposes that the heterogeneity of nascent particles with respect to lipid composition, diameter and number of ApoA-I molecules may be determined by the specific membrane microenvironment that is solubilized. Because ABCA1 is expressed in neurons as well as glia, it is possible that exovasiculated domains generated in these two cell types may produce a distinct repertoire of nascent ApoE-HDL particles in the brain that have discrete effects on Aβ metabolism.

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    . Mechanism of ATP-binding cassette transporter A1-mediated cellular lipid efflux to apolipoprotein A-I and formation of high density lipoprotein particles. J Biol Chem. 2007 Aug 24;282(34):25123-30. PubMed.