The cell cholesterol exporter ABCA1 as a protector from cardiovascular disease and diabetes

Biochimica et Biophysica Acta 1791 (2009) 563–572

Contents lists available at ScienceDirect

Biochimica et Biophysica Acta j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / b b a l i p

Review

The cell cholesterol exporter ABCA1 as a protector from cardiovascular disease and diabetes Chongren Tang ⁎, John F. Oram 1 Department of Medicine, University of Washington, Seattle, Washington, USA

a r t i c l e

i n f o

Article history: Received 22 January 2009 Received in revised form 17 March 2009 Accepted 17 March 2009 Available online 1 April 2009 Keywords: ABCA1 Cell cholesterol export HDL Apolipoprotein A-I Inflammation Macrophage Cardiovascular disease Diabetes

a b s t r a c t ATP-binding cassette transporter A1 (ABCA1) is an integral cell membrane protein that exports cholesterol from cells and suppresses macrophage inflammation. ABCA1 exports cholesterol by a multistep pathway that involves forming cell-surface lipid domains, solubilizing these lipids by apolipoproteins, binding of apolipoproteins to ABCA1, and activating signaling processes. Thus, ABCA1 behaves both as a lipid exporter and a signaling receptor. ABCA1 transcription is highly induced by sterols, and its expression and activity are regulated post-transcriptionally by diverse processes. ABCA1 mutations can reduce plasma HDL levels, accelerate cardiovascular disease, and increase the risk for type 2 diabetes. Genetic manipulations of ABCA1 expression in mice also affect plasma HDL levels, inflammation, atherogenesis, and pancreatic β cell function. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and decrease cholesterol export from macrophages, raising the possibility that an impaired ABCA1 pathway contributes to the enhanced atherogenesis associated with common inflammatory and metabolic disorders. The ABCA1 pathway has therefore become a promising new therapeutic target for treating cardiovascular disease and diabetes. © 2009 Elsevier B.V. All rights reserved.

1. Introduction Cholesterol is an abundant metabolite in mammalian tissues that is essential for several biological systems. Membrane fluidity of all cells is controlled by the ordered packing of cholesterol between phospholipid molecules. Cholesterol also concentrates in sphingolipid-rich domains of the plasma membrane called rafts that contain a variety of important receptors and signaling molecules [1]. In addition, cholesterol is a substrate for steroid production and covalently links to a cell morphogen required for normal embryonic development and cell differentiation [2]. Too much cholesterol, however, can have pathological consequences. Because cholesterol is poorly soluble in water and seeks a lipid environment, an uncontrolled build up of cholesterol in cells can disrupt membranes and cause cytotoxicity [3]. Accumulation of excess cholesterol causes atherosclerotic cardiovascular disease (CVD) [4] and might contribute to the early onset of Alzheimer's disease [5] and renal dysfunction [6,7]. Cells therefore rely on a complex homeostatic network to modulate the availability of cholesterol.

⁎ Corresponding author. E-mail addresses: [email protected] (C. Tang), [email protected] (J.F. Oram). 1 Mailing address: Metabolism, Box 358055, University of Washington, Seattle, WA 98195-8055, USA. Tel.: +1 206 543 8406; fax: +1 206 685 3781. 1388-1981/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2009.03.011

Cells other than those in steroidogenic tissues and the liver cannot catabolize cholesterol. Instead they modulate their membrane cholesterol content by a feedback system that controls the rate of cholesterol biosynthesis and uptake by the low-density lipoprotein (LDL) receptor. With most cell types this system is sufficient to provide cells with enough cholesterol for cellular functions without overloading them. Macrophages, however, can ingest membrane- or lipoprotein-derived cholesterol by endocytotic and phagocytotic pathways that are not feedback regulated by cholesterol. These cells must either store this excess cholesterol as esters in lipid droplets or export it. A subfraction of circulating lipoproteins called high-density lipoproteins (HDLs) is involved in the export of excess cholesterol from cells. One of the major functions of HDL is to transport cholesterol from peripheral tissues to the liver for elimination in the bile [8]. It is believed that the removal of excess cholesterol from arterial macrophages contributes to the well-established cardioprotective effects of HDL. HDL components can remove cellular cholesterol by multiple mechanisms [9]. HDL phospholipids absorb cholesterol that diffuses from the plasma membrane into the aqueous phase, a passive process that is facilitated by the interaction of HDL particles with scavenger receptor B1. Three cell membrane transporters have been identified that mediate cholesterol efflux from cells to HDL components by metabolically active pathways. All three belong to a superfamily of ATP-binding cassette transporters (ABCs) [10]. ABCA1 mediates the transport of cellular cholesterol, phospholipids, and other metabolites

564

C. Tang, J.F. Oram / Biochimica et Biophysica Acta 1791 (2009) 563–572

2.2. Substrates and acceptors

Fig. 1. Topological model of ABCA1. NBD-1 and NBD-2 are the nucleotide binding domains that contain the highly conserved Walker A and Walker B domains and the signature C motifs. EC1 and EC2 are the extracellular loops.

to HDL proteins (apolipoproteins) that are associated with no or very little lipid [11–14]. ABCA1 is highly expressed in the liver and tissue macrophages. ABCG1 and ABCG4 mediate cholesterol transport from cells to HDL particles and other lipoproteins [15–19]. ABCG1 is also highly expressed in macrophages and may work synergistically with ABCA1 to remove excess cholesterol [19,20]. ABCG4 appears to be selectively expressed in brain cells where it may have a specialized lipid transport function [16]. ABCA1 is one of the most extensively characterized ABC transporters. Numerous studies of cultured cells, human HDL deficiencies, and animal models have shown that ABCA1 is an efficient exporter of cholesterol from macrophages and other cells, a major determinant of plasma HDL levels, and a potent cardioprotective factor. This transporter has therefore become a new therapeutic target for drug development designed for clearing cholesterol from arterial macrophages and preventing CVD. This review will focus on the biology and pathophysiology of ABCA1. 2. Cell biology 2.1. Structure and function ABCA1 is a 2261-amino-acid integral membrane protein that comprises two halves of similar structure (Fig. 1) [21]. Each half has a transmembrane domain containing six helices and a nucleotide binding domain (NBD) containing two conserved peptide motifs known as Walker A and Walker B, which are present in many proteins that utilize ATP, and a Walker C signature unique to ABC transporters [10]. ABCA1 is predicted to have an N-terminus oriented into the cytosol and two large extracellular loops that are highly glycosylated and may be linked by one or more cysteine bonds. ABCA1 mediates the transport of cholesterol, phospholipids, and other lipophilic molecules across cellular membranes, where they are removed from cells by lipid-poor HDL apolipoproteins [12,22]. These partially lipidated apolipoproteins can then acquire additional cholesterol by other processes and mature into spherical HDL particles. It is likely that ABCA1 forms a channel in the membrane that promotes flipping of lipids from the inner to outer membrane leaflet by an ATPase-dependent process. ABCA1 localizes to the plasma membrane and intracellular compartments [23–25], where it could potentially facilitate transport of lipids to either cell surface-bound or internalized apolipoproteins. Recent studies, however, have suggested that ABCA1 transports cholesterol to apolipoproteins exclusively at the cell surface [26–28]. The lipid export function of ABCA1 appears to depend on the formation of oligomers [29,30].

ABCA1 can promote phospholipid efflux from cholesterol-depleted cells in the presence of apolipoproteins [31,32], suggesting that phospholipids, particularly phosphatidylcholines [33,34], are the primary ABCA1substrates. ABCA1 also appears to translocate phosphatidylserine to the exofacial side of the plasma membrane [35], which may promote engulfment of apoptotic cells by macrophages [36] and generation of microparticles that bleb from plasma membranes [37–39]. ABCA1 has been reported to export substrates other than cholesterol and phospholipids, including α-tocopherol [40], apoE [41], and interleukin-1β [42,43]. It is possible that apolipoproteins can pick up several types of lipophilic molecules that localize to phospholipid-rich domains formed by ABCA1 on the cell surface. Apolipoproteins must be associated with no or very little lipid to be acceptors for ABCA1-exported substrates [44,45]. This acceptor activity has a broad specificity for multiple HDL apolipoproteins, including apos AI, AII, E, CI, CII, CIII, and AIV [46]. These apolipoproteins contain 11–22 amino acid repeats of amphipathic α-helices [47]. In this type of helix, the charged amino acids align along one face of the long axis while the hydrophobic residues align along the other face. The most abundant apolipoprotein in HDL is apoA-I, which comprises 60–70% of the total HDL protein mass. ApoA-I contains eight 22-amino acid and two 11-amino acid tandem amphipathic αhelical domains. ApoA-I is the most physiologically relevant lipid acceptor for ABCA1 because of its high abundance, its role as the major template for forming nascent HDL particles, and its ability to dissociate from mature HDL particles to regenerate lipid-poor acceptors. Synthetic 18 amino acid peptides that are analogs of the type of amphipathic α-helices found in HDL apolipoproteins can mimic apoAI in removing cholesterol and phospholipids by the ABCA1 pathway [48–51]. A dimer of one of these peptides is more efficacious than its monomer [48,50,51], suggesting cooperativity between tandem helices. Thus, the amphipathic α-helix is the major structural motif required for removing ABCA1-extruded lipids. Interestingly, the Disomers of these α-helices are also active [49,52], implying that there are no stereoselective requirements for these peptides to accept lipids. The broad specificity for amphipathic α-helices implies that proteins other than apolipoproteins containing this structural motif could remove cellular lipids by the ABCA1 pathway. Phospholipid transfer protein (PLTP), which contains amphipathic α-helices, can interact with ABCA1 and remove cellular cholesterol and phospholipids [53,54]. Because of its low lipid binding capacity, PLTP tends to transfer these lipids to HDL rather than generate new lipoprotein particles. Serum amyloid A (SAA) also removes cellular lipids by the ABCA1 pathway [55]. SAA is an acute phase protein that is induced over 1000-fold during inflammation [56]. SAA mostly associates with HDL in the plasma. It contains two tandem amphipathic α-helices that differ in amino acid charge distribution from those in apolipoproteins. The consequences of SAA interactions with ABCA1 are unknown. 2.3. Regulation of expression ABCA1 protein levels are highly regulated by multiple processes [12]. In keeping with its cholesterol export function, transcription of ABCA1 is markedly induced by overloading cells with cholesterol [57,58]. This induction occurs through the nuclear receptors liver X receptor (LXRα and/or LXRβ) and retinoid X receptor (RXR) [59,60]. LXR and RXR form heterodimers that preferentially bind to response elements within the ABCA1 gene promoter and the first intron. LXR and RXR bind to and are activated by oxysterols and retinoic acid, respectively [61]. Binding of either one or both ligands can activate transcription. Treatment of cells with either an oxysterol or 9-cisretinoic acid induces ABCA1, but their combined treatment has

C. Tang, J.F. Oram / Biochimica et Biophysica Acta 1791 (2009) 563–572

additive effects [59,60]. Excess intracellular cholesterol is converted to an oxysterol, which regulates ABCA1 and other cholesterol homeostatic processes [62,63]. Metabolites other than sterols can modulate ABCA1 expression through the LXR system, and factors independent of LXR/RXR can also regulate ABCA1 transcription [12]. One study showed a high degree of discordance between ABCA1 mRNA and protein levels in mouse tissues [64], implying that ABCA1 is highly regulated post-transcriptionally in vivo. Several processes that modulate ABCA1 mRNA and protein stability have been described. When ABCA1 inducers are removed in the absence of apolipoproteins, ABCA1 mRNA and protein are degraded at a fast rate (half-life of 1– 2 h) [65–67]. IFNγ appears to suppress ABCA1 expression by further destabilizing its mRNA [68]. The interaction of apolipoproteins with ABCA1-expressing cells dramatically reduces the rate of ABCA1 protein degradation by inhibiting ABCA1 proteolysis by calpain [66] and activating other signaling events that stabilize the protein [52]. This regulation acts as a feedback mechanism to sustain ABCA1 levels when acceptors for cellular lipids are available. Unsaturated free fatty acids directly destabilize ABCA1 protein in cultured cells by a signaling pathway involving activation of phospholipase D2 and protein kinase Cδ and phosphorylation of ABCA1 serines [67,69–71]. It is likely that many other processes that regulate ABCA1 expression will be discovered in future studies. 2.4. Receptor-like activity ABCA1 is unique among eukaryotic ABC transporters in that it requires the direct binding of the acceptor for the transported substrate. Covalent cross-linking studies revealed that apolipoproteins bind directly to ABCA1 with saturability and high-affinity (Kd b 10− 7 M) [72,73]. As with lipid export, the ABCA1 binding determinant of apolipoproteins is the amphipathic α-helix. This binding may be mediated by the large extracellular loops of ABCA1, which are unique for this family of transporters. This binding is not required for the intrinsic lipid transport activity of ABCA1, as forced overexpression of ABCA1 increases lipid domains on the cell surface in the absence of apolipoproteins [31,74]. Instead, the binding appears to facilitate the removal of these lipids, perhaps by targeting apolipoproteins to ABCA1-generated lipid domains. The interaction of apolipoproteins with ABCA1-expressing cells also activates signaling molecules that modulate ABCA1 expression or lipid transport activity. These include Janis kinase 2 (JAK2) [50,74], protein kinase C [75], Cdc42, and other protein kinases [76]. Although it remains to be shown that these activation steps involve direct binding of apolipoproteins to ABCA1, these findings suggest that apolipoprotein/ABCA1 interactions behave like a ligand/receptor system. The best characterized signaling molecule activated by apolipoprotein/ABCA1 interactions is JAK2, a tyrosine kinase that is activated by over half of the cytokine/hematopoietin superfamily of receptors [77]. Activation of JAK2 is the initiating step in down-stream signaling for most of these receptors. A JAK2-specific inhibitor markedly reduces apoA-I-mediated lipid transport and apoA-I binding to ABCA1, and mutant cells lacking JAK2 have a severely impaired ABCA1 pathway [50,74]. Inhibiting or ablating JAK2 has no effect on the intrinsic lipid translocase activity of ABCA1 but reduces the apolipoprotein binding to ABCA1 required for removal of the translocated lipids. Activation of JAK2 has the same broad specificity for amphipathic α-helices as removal of cell lipids [50]. Studies of ABCA1 mutants with variable severities of functional impairment showed that apolipoprotein-stimulated phosphorylation of JAK2 was highly correlated with both the lipid export and apolipoprotein binding activities of ABCA1 [78]. Thus, the JAK2 signaling pathway plays a critical role in optimizing ABCA1 activity. The interaction of apoA-I with ABCA1-expressing cells for only minutes stimulates autophosphorylation of JAK2 [50], thus generating

565

the active JAK2 that phosphorylates its target proteins. This suggests that apolipoproteins potentiate their own interactions with ABCA1 by activating JAK2, which in turn increases the apolipoprotein binding to ABCA1 required for lipid removal. This type of JAK2-mediated feedforward mechanism has not been described for any other transporter. For receptor systems, phosphorylated JAK2 activates down-stream transcription factors called STATs, which regulate a wide variety of cellular pathways. The interaction of apoA-I with ABCA1 increases phosphorylation and thus activation of STAT3, and this appears to have effects unrelated to lipid transport [79]. These studies raise the possibility that apolipoprotein/ABCA1 interactions may have multiple biological effects that are lipid export dependent and independent. 2.5. Anti-inflammatory activity Mouse lacking ABCA1 in all tissues or specifically in macrophages has a heightened response to treatment with the inflammatory stimulus lipopolysaccaride (LPS) [80]. This was evident by the increased appearance of inflammatory cytokines in the circulation and peritoneal fluid after mice were injected with LPS. These studies imply that macrophage ABCA1 has an anti-inflammatory function. Studies with cultured cells have suggested that the anti-inflammatory activity of ABCA1 is secondary to its ability to modulate the cholesterol content of membrane lipid rafts. Murine macrophages lacking ABCA1 have an increased cholesterol content in rafts and enhanced signaling of LPS though its receptor, TLR4, which stimulates production of inflammatory cytokines [80–83]. Incubating human monocytes with apoA-I reduces the ability of inflammatory stimuli to activate CD11b, and this is abolished in cells lacking ABCA1 [84]. ApoA-I also was shown to activate the raft-associated metalloprotease ADAM17 [85], which promotes proteolytic shedding of the proinflammatory cytokine TNFα and its receptors. All these responses appear to depend on the cholesterol content of plasma membrane rafts. These anti-inflammatory effects are not specific to ABCA1, as ABCA1-independent cholesterol acceptors such as HDL or cyclodextrin have the same effects. Moreover, the macrophage cholesterol exporter ABCG1, which promotes cholesterol efflux to HDL, has a more potent anti-inflammatory effect than ABCA1 in mice [83]. However, studies showing that apolipoprotein/ABCA1 interactions activate the JAK2/STAT3 pathway [79], which is anti-inflammatory in macrophages [86–88], raise the possibility that ABCA1 could suppress inflammation independent of its effects on lipid rafts. Additional work is needed to understand the important role of ABCA1 in suppressing macrophage inflammation. 2.6. Lipid transport model It is still unclear how ABCA1 and most other ABC transporters translocate their substrates across membranes. Electron microscopy and X-ray crystallography analyses of a limited number of ABC exporters suggest that the two symmetrical transmembrane bundles come together to form a chamber that scans the inner leaflet of the membrane for substrates, incorporates them into the chamber, and flips them to the outer leaflet for extrusion from the cell [89–91] (Fig. 2). This involves a series of conformational changes in the ABC protein that is driven by ATP hydrolysis in the NBD domains. In the case of ABCA1, amino acid motifs in the chamber are likely to bind phospholipids. It is unknown whether inner leaflet cholesterol is cotransported with these phospholipids or phospholipid translocation alone increases the accessibility of cholesterol that flips to the outer leaflet by other processes. The observation that ABCA1 can affect the cholesterol content of lipid rafts, which probably relies on lateral diffusion of cholesterol along the membrane, supports the idea that ABCA1 also translocates cholesterol.

566

C. Tang, J.F. Oram / Biochimica et Biophysica Acta 1791 (2009) 563–572

Fig. 2. Model for the lipid export activity of ABCA1. (A) Phospholipids (PL) and perhaps free cholesterol (C) are translocated across the plasma membrane (striped band) to form tightly packed and disordered lipid domains that protrude from the cells. (B) ApoA-I binds to ABCA1 and stimulates phosphorylation (-P) of JAK2. (C) The phosphorylated/activated JAK2 enhances the apoA-I binding to ABCA1 required for interaction with lipid domains generated by ABCA1. (D) ApoA-I solubilizes the lipids to form nascent HDL particles (discs).

Studies from several laboratories suggest the following model for the ABCA1-dependent lipid export pathway. When induced by cholesterol loading of cells, ABCA1 constitutively generates cholesterol- and phospholipid-rich membrane domains, even in the absence of apolipoproteins [31] (Fig. 2A). These domains bend from the plasma membrane to relieve the strain of the densely packed phospholipids, generating curved and disordered lipid surfaces that favor apolipoprotein interactions [92,93]. During the first several minutes of exposure to apolipoproteins, JAK2 is activated by autophosphorylation (Fig. 2B), which in turn increases binding of apolipoproteins to ABCA1 (Fig. 2C) [50,74,78]. This binding facilitates the interaction of apoA-I with the protruding lipid domains, promoting their solubilization and release from the cells [93–95] (Fig. 2D). Activation of JAK2 could also affect transcription of genes that encode proteins that have other effects on cellular pathways. The interaction of apoA-I with cells stabilizes ABCA1 protein, but mostly through binding sites distinct from those promoting lipid export [50,54]. This energy-driven pathway is a very efficient process for ridding cells of excess cholesterol and perhaps modulating other cellular pathways. 3. Pathophysiology 3.1. Gene variants Over 70 mutations in ABCA1 have been identified in subjects with low plasma HDL levels, more than half of which are missense mutations [96–99]. Although these mutations occur throughout the gene, they tend to cluster in the extracellular loops, the NBD domains, and the C-terminal region. The initial loss-of-function mutations in ABCA1 were discovered in case reports and family studies. More recently, rare and common gene variations were identified by screening ABCA1 from subjects

with low plasma HDL levels for single nucleotide polymorphisms (SNPs) [96–99]. Most of the identified rare alleles (mutations) were absent in populations of subjects with high HDL levels [97,98], implying that they play a causative role in lowering HDL levels. Some mutations, however, were found to be more frequent in subjects with the highest HDL levels, consistent with an enhancement of the ABCA1 pathway. Based on mutation frequency in those with the lowest 1% of HDL cholesterol, it was estimated that 10–15% of the HDL deficient individuals in the general population are heterozygous for ABCA1 mutations [98]. These observations are consistent with ABCA1 being a determinant of plasma HDL levels in humans. This conclusion was further supported by studies showing that the degree of cholesterol efflux from cells with a specific ABCA1 missense mutation correlated with the severity of the HDL deficiency in subjects having this mutation [100–102]. SNP analyses have identified over twenty common polymorphisms (N1% allelic frequency) in the coding, promoter, and 5′UTR regions of ABCA1, and several of these are associated with either low or high plasma HDL levels [96,99]. Studies of animal models have provided additional evidence that ABCA1 is a major determinant of plasma HDL levels. Targeted disruption of the Abca1 gene in mice produces a severe HDL deficiency, similar to that seen in humans with homozygous or compound heterozygous loss-of-function ABCA1 mutations [103]. Conversely, overexpressing ABCA1 in mice elevates plasma HDL levels [104–106]. The liver ABCA1 pathway in mice appears to be responsible for generating most of the plasma HDL. Selective hyperexpression of ABCA1 in mouse livers markedly increases plasma HDL levels [107], and targeted disruption of mouse liver ABCA1 reduces plasma HDL levels by 80% [108]. These observations imply that the major cause of the HDL deficiency in subjects with ABCA1 mutations and in ABCA1 knockout mice is an impaired liver ABCA1 pathway. Targeted ablation

C. Tang, J.F. Oram / Biochimica et Biophysica Acta 1791 (2009) 563–572

of mouse intestinal ABCA1 also modestly but significantly reduces plasma HDL levels [109,110]. 3.2. Cardiovascular disease Numerous population studies have shown an inverse relationship between plasma HDL levels and CVD risk, implying that HDL protects against atherosclerosis. Although there are multiple mechanisms by which HDL can be cardioprotective, it is clear that the relative activity of ABCA1 plays a role. Genetic and cell biology studies suggest that low plasma HDL levels in many individuals reflects an impaired ABCA1 pathway, which would also promote accumulation of cholesterol in tissue macrophages and perhaps increase local inflammation. Accumulation of sterol-laden macrophage “foam cells” in the artery wall and triggering inflammation are early events in formation of atherosclerotic lesions. Thus, the relative activity of the cellular ABCA1 pathway in arterial macrophages would be expected to have a major impact on atherogenesis. Subjects with loss-of-function homozygous or compound heterozygous mutations in ABCA1 (Tangier disease) have a 4–6-fold higher than normal incidence of CVD [111], which applies equally to both men and women. This moderately high risk for atherosclerosis is not as dramatic as one would expect for individuals with a virtual absence of HDL, a well-known cardioprotective lipoprotein. Their low levels of LDL (40–60% normal) may partially protect these subjects from atherogenesis. Some subjects with common ABCA1 variants have been reported to have premature CVD [96,112]. However, the number of identified Tangier disease patients is very low (∼ 100), and not all individuals with the same ABCA1 variant show signs of CVD. Therefore, it is difficult to draw firm conclusions about the cardioprotective role of ABCA1 from this limited number of case reports. Studies of ABCA1 heterozygotes, who tend to have more normal levels of LDL, have produced ambiguous results. Analyses of a small number of Tangier disease heterozygotes showed significant increases in CVD and carotid artery intima media thickness when compared to control subjects, and these increases were associated with impaired ABCA1-dependent cholesterol efflux from their cultured fibroblasts [100,102]. A study of the Copenhagen City Heart cohort revealed that genetic variations in ABCA1 affect CVD in the general population [112]. A follow up study of the same cohort, however, concluded that the low HDL levels associated with ABCA1 variants do not predict premature CVD [113]. It was also reported that common variations in ABCA1 are associated with increased CVD despite normal HDL levels [96,112,114]. These studies strongly support the idea that impaired ABCA1 increases atherosclerosis in humans, but not in all cases and by mechanisms that may not reflect reduced HDL levels. There are several possible reasons for these variable responses to ABCA1 mutations. First, many of the ABCA1 heterozygotes have only modest reductions in plasma HDL levels and ABCA1 cholesterol export activities, and thus the defects may not be significant enough to accelerate CVD in all individuals. Second, most of the HDL is produced by liver ABCA1, which may not reflect the activity of ABCA1 in arterial macrophages. Third, impairment of other ABCA1 functions, such as anti-inflammation, could have bigger impacts on atherogenesis than reduced cholesterol export, especially in individuals prone to enhanced inflammatory responses. These genetic studies are likely to grossly underestimate the contribution of impaired ABCA1 to premature CVD in the general population. If mice data can be extrapolated to humans [64], ABCA1 protein levels and activity would be mostly controlled by posttranscriptional processes. Thus, atherogenic factors could impair ABCA1 function independent of gene regulation. Mouse model studies have provided the strongest support for the cardioprotective effects of macrophage ABCA1. Some but not all

567

reports showed that overexpression of human ABCA1 in mice significantly reduced diet-induced atherosclerosis in association with a favorable change in lipoprotein profile [106,115]. Reciprocal bone marrow transplantation studies using wild-type and Abca1 null mice have shown that selectively over- or under-expressing ABCA1 in macrophages decreases or increases atherogenesis, respectively [116–118]. 3.3. Diabetes There is mounting evidence that ABCA1 plays a role in protection against diabetes [119]. Mice lacking Abca1 have impaired glucose tolerance with normal insulin sensitivity [120], consistent with a defect in pancreatic β-cell function. Abca1 is highly expressed in islet β cells, and selective ablation of Abca1 in β cells increases their cholesterol content. Islets from these animals have reduced glucose-stimulated insulin secretion, suggesting that the increased cell cholesterol caused by the absence of ABCA1 impairs islet function. This idea was supported by studies showing that mice lacking β-cell ABCA1 had normal plasma cholesterol and fasting glucose levels but impaired glucose tolerance and reduced insulin secretion [120]. Additional evidence for a diabetes protective effect of ABCA1 comes from studies of mice administered the thiazolidinedione drug rosiglitazone. In humans, rosiglitazone is used to treat insulin resistance and improve β-cell function [121]. Rosiglitazone activates the transcriptional factor PPARγ, which stimulates transcription of several genes in insulin-responsive cells [122]. PPARγ also activates ABCA1 transcription through LXR [123,124]. In mice fed a high-fat diet, rosiglitazone improves glucose tolerance, but these beneficial effects disappear when Abca1 is ablated in β cells [120]. These findings suggest that β-cell ABCA1 contributes to the insulin sensitizing effects of thiazolidinediones. There is genetic evidence that ABCA1 is involved in modulating type 2 diabetes in humans. Several ABCA1 polymorphisms and mutations are associated with type 2 diabetes across multiple ethnic groups [119]. In particular, subjects with the R230C polymorphism in the Mexican population have low HDL, increased body mass, elevated hemoglobin A1c levels, reduced fasting insulin, and early onset type 2 diabetes [125–128]. Impaired ABCA1 may play a role in the macrovascular complication of diabetes. CVD is the major cause of morbidity and mortality in both types 1 and 2 diabetes [129–132]. Low plasma HDL is one of the CVD risk factors associated with type 2 diabetes and metabolic syndrome [129,133–136]. The HDL particle distribution is abnormal in both types 1 and 2 diabetes, with decreases in the relative fraction of the large HDL particles believed to be cardioprotective [129,137]. These results raise the possibility that abnormal HDL metabolism contributes to the increased CVD caused by diabetes and the metabolic syndrome. Since ABCA1 is a major determinant of plasma HDL and CVD, diabetes-induced impairment of this transporter may contribute to these complications. Two features of diabetes and the metabolic syndrome are elevated glucose and fatty acids [138,139]. Prolonged hyperglycemia can generate small reactive carbonyls that form destructive advanced glycated end products (AGEs) on tissue proteins [140– 142]. The reactive carbonyls glyoxal and glycoaldehyde acutely and severely impair the ABCA1 pathway in cultured macrophages, presumably by directly damaging ABCA1 protein [143]. In addition, fatty acids destabilize ABCA1 protein by activating a signaling pathway that phosphorylates ABCA1 and enhances its degradation [67,69–71]. In swine and mouse models of diabetes, inducing type 1 diabetes selectively reduces ABCA1 protein in macrophages without affecting mRNA levels, consistent with the idea that factors associated with diabetes destabilize ABCA1 protein [144,145]. Moreover, destabilizing ABCA1 protein in β

568

C. Tang, J.F. Oram / Biochimica et Biophysica Acta 1791 (2009) 563–572

cells may further accelerate type 2 diabetes by impairing insulin production [119]. 4. Pharmacology The studies described above have provided strong evidence that ABCA1 plays an important role in protection against CVD, metabolic syndrome, and type 2 diabetes, the most common debilitating diseases in the Western world. ABCA1 has therefore become a promising new therapeutic target for these disorders, and multiple programs have been initiated by the pharmaceutical industry to develop agonists for this pathway. These programs are based on the assumption that an increased ABCA1 activity in arterial macrophages would prevent foam-cell atherosclerotic lesion formation and suppress damaging inflammation, that an increased liver ABCA1 activity would elevate plasma levels of cardioprotective HDL, and that activated β-cell ABCA1 would stimulate insulin production. The activity of the ABCA1 pathway can be modulated at multiple levels, providing an array of potential therapeutic targets for enhancing this pathway. 4.1. Transcription Because of the robust induction of ABCA1 by sterols, most of the therapeutic approaches for enhancing ABCA1 activity have focused on generating LXR agonists that induce ABCA1 transcription, and several of these have been developed and characterized. An additional advantage of these agonists is that they induce other proteins involved in several steps along the reverse cholesterol transport pathway: ABCG1 [17], which mediates cholesterol efflux to HDL particles [18]; apoE [146], which promotes cholesterol efflux from macrophages by both ABCA1-independent and -dependent mechanisms [147]; and liver and intestinal ABCG5 and ABCG8 [148], which promote excretion of liver and dietary cholesterol into the bile [149]. Thus, LXR agonists have the potential for activating multiple processes that coordinate excretion of excess cholesterol from the body. Two non-steroidal synthetic LXR agonists (TO901317 and GW3965) have been shown to increase plasma HDL levels and reduce atherosclerosis in mouse models [150–152]. A limitation to the first generation LXR agonists is that they increase hepatic fatty acid synthesis and esterification and thus generate fatty livers and hypertriglyceridemia when administered to animals [153,154]. LXR agonists induce fatty acid synthase and a transcriptional factor named sterol regulatory binding element protein-1c (SREBP-1c) that activates genes for several enzymes in the fatty acid biosynthetic pathway [155]. A major challenge is to produce potent synthetic LXR agonists that selectively induce ABCA1 and other cholesterol transporters. Agonists for RXR, the heterodimeric partner for LXR, also stimulate ABCA1 transcription in cultured cells [59,60]. Administration of an RXR agonist to atherosclerotic mice was shown to reduce atherosclerosis [156]. The limitation for this class of agonists is that RXR forms active heterodimers with several other nuclear receptors that control many different metabolic pathways. LXRs have therefore been the preferred target for modulating ABCA1 expression. It was reported, however, that retinoic acid receptor activators can induce ABCA1 without affecting other LXR-targeted genes [157], raising the possibility of selective drug therapy through the RXR system. 4.2. Post-transcription Another potential limitation in therapeutic targeting of ABCA1 transcription is that ABCA1 protein levels and activity are highly regulated by post-transcriptional processes. Agonists that stimulate ABCA1 transcription may have a limited ability to enhance the ABCA1 pathway if other factors control protein levels and activity. To date, the

most promising approach for modulating ABCA1 protein levels and activity involves developing peptides and other small molecular agonists that interact with ABCA1. As discussed above, several 18- and 37-mer amphipathic α-helical peptides have been produced that mimic the interactions of apolipoproteins with ABCA1, including directly binding to ABCA1, removing lipids, activating JAK2, and stabilizing ABCA1 protein [49,50,52,73]. One of these 18-mer peptides, called 4-F because of its 4 phenylalanines, has been shown to reduce atherosclerosis, obesity, and insulin resistance when injected into mouse models [158,159]. An isomer of this peptide containing only D-amino acids (D4F) is absorbed orally into the blood stream of mice where it has a low rate of turnover [160]. Administration of this peptide in the drinking water was shown to markedly reduce atherosclerosis in animal models [160]. These effects were associated with an increase in the anti-inflammatory properties of HDL particles, improved vascular function, and an enhanced cholesterol efflux from macrophages [161– 163], suggesting that D-4F protects against atherosclerosis by several mechanisms, including possible interactions with ABCA1. The potential advantage of these peptides over full-length apolipoproteins is that they can be given orally and are long-lived. Another advantage is that they may be relatively resistant to the oxidative damage reported to impair the interaction of apoA-I with ABCA1 [164,165]. A disadvantage is that they also have non-specific detergent effects on membrane lipids and can accumulate in tissues and damage cells [49,50,166]. Recently an analog of the 37-mer peptide was developed, with alanines substituted for lipophilic amino acids, that specifically removes cellular cholesterol by the ABCA1 pathway without having detergent-like effects [166]. These studies support the concept that peptides and other small apolipoproteinmimetic molecules could be valuable therapeutic agents for treating CVD and the metabolic syndrome. 5. Conclusions and future directions Studies of human HDL deficiencies, transgenic mice, and cultured cells have shown that ABCA1 is the major exporter of cellular cholesterol and phospholipids to HDL apolipoproteins, and that this activity is essential for formation of HDL particles in vivo. There is emerging evidence that ABCA1 also plays a role in suppressing inflammatory cytokine production by macrophages through multiple mechanisms. ABCA1 is unique among transporters in that its interaction with apolipoproteins has receptor-like properties. In addition to removing lipids, binding of apolipoproteins to ABCA1 activates signaling molecules such as JAK2 that optimize the lipid export activity of ABCA1 and regulate other processes important for cell biology. ABCA1 expression and activity are highly regulated by transcriptional and post-transcriptional mechanisms. Although transcriptional induction by sterols conforms to its role as a cholesterol exporter, the biological relevance of other regulatory processes are still unclear. Human genetic and mouse model studies have shown that ABCA1 is cardioprotective and essential for normal pancreatic β cell function. This has made ABCA1 a promising new therapeutic target for CVD and type 2 diabetes, and strategies have been developed that target transcriptional and post-transcriptional regulation of ABCA1 expression and activity. The observation that ABCA1 functions as a signaling receptor may suggest new treatment protocols for these and other inflammatory disorders. Although we have gained great deal of knowledge about the function of ABCA1 since its discovery in 1999, the ABCA1 pathway is highly complex and far from being completely understood. Additional studies are needed to identify the molecular components of the ABCA1 pathway, to characterize the receptor-like properties of ABCA1 and its anti-inflammatory activity, to elucidate the diverse processes that regulate ABCA1 expression and activity, and to determine its

C. Tang, J.F. Oram / Biochimica et Biophysica Acta 1791 (2009) 563–572

contribution to disease protection in humans. These studies will provide more insight into the role of ABCA1 in health and disease and will reveal novel therapeutic strategies for treating these diseases. Acknowledgements The authors' work described in this review was supported by National Institutes of Health grants HL18645, HL075340, HL55362, and DK02456. References [1] L.J. Pike, Lipid rafts: heterogeneity on the high seas, Biochem. J. 378 (2004) 281–292. [2] P.M. Lewis, M.P. Dunn, J.A. McMahon, M. Logan, J.F. Martin, B. St-Jacques, A.P. McMahon, Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1, Cell 105 (2001) 599–612. [3] B. Feng, P.M. Yao, Y. Li, C.M. Devlin, D. Zhang, H.P. Harding, M. Sweeney, J.X. Rong, G. Kuriakose, E.A. Fisher, A.R. Marks, D. Ron, I. Tabas, The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages, Nat. Cell Biol. 5 (2003) 781–792. [4] J.R. Guyton, K.F. Klemp, Development of the lipid-rich core in human atherosclerosis, Arterioscler. Thromb. Vasc. Biol. 16 (1996) 4–11. [5] C.L. Wellington, Cholesterol at the crossroads: Alzheimer's disease and lipid metabolism, Clin. Genet. 66 (2004) 1–16. [6] C.K. Abrass, Cellular lipid metabolism and the role of lipids in progressive renal disease, Am. J. Nephrol. 24 (2004) 46–53. [7] D. Kees-Folts, J.R. Diamond, Relationship between hyperlipidemia, lipid mediators, and progressive glomerulosclerosis in the nephrotic syndrome, Am. J. Nephrol. 13 (1993) 365–375. [8] C.J. Fielding, P.E. Fielding, Molecular physiology of reverse cholesterol transport, J. Lipid Res. 36 (1995) 211–228. [9] G.H. Rothblat, M. de la Llera-Moya, V. Atger, G. Kellner-Weibel, D.L. Williams, M.C. Phillips, Cell cholesterol efflux: integration of old and new observations provides new insights, J. Lipid Res. 40 (1999) 781–796. [10] M. Dean, Y. Hamon, G. Chimini, The human ATP-binding cassette (ABC) transporter superfamily, J. Lipid Res. 42 (2001) 1007–1017. [11] J.F. Oram, HDL Apolipoproteins and ABCA1: partners in the removal of excess cellular cholesterol, Arterioscler. Thromb. Vasc. Biol. 23 (2003) 720–727. [12] J.F. Oram, J.W. Heinecke, ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease, Physiol. Rev. 85 (2005) 1343–1372. [13] A.R. Tall, ATVB in focus: role of ABCA1 in cellular cholesterol efflux and reverse cholesterol transport, Arterioscler. Thromb. Vasc. Biol. 23 (2003) 710–711. [14] G.H. Rothblat, F.H. Mahlberg, W.J. Johnson, M.C. Phillips, Apolipoproteins, membrane cholesterol domains, and the regulation of cholesterol efflux, J. Lipid Res. 33 (1992) 1091–1097. [15] K. Nakamura, M.A. Kennedy, A. Baldan, D.D. Bojanic, K. Lyons, P.A. Edwards, Expression and regulation of multiple murine ATP-binding cassette transporter G1 mRNAs/isoforms that stimulate cellular cholesterol efflux to high density lipoprotein, J. Biol. Chem. 279 (2004) 45980–45989. [16] S. Oldfield, C. Lowry, J. Ruddick, S. Lightman, ABCG4: a novel human white family ABC-transporter expressed in the brain and eye, Biochim. Biophys. Acta 1591 (2002) 175–179. [17] G. Schmitz, T. Langmann, S. Heimerl, Role of ABCG1 and other ABCG family members in lipid metabolism, J. Lipid Res. 42 (2001) 1513–1520. [18] N. Wang, D. Lan, W. Chen, F. Matsuura, A.R. Tall, ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins, Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 9774–9779. [19] A.M. Vaughan, J.F. Oram, ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL, J. Lipid Res. 47 (2006) 2433–2443. [20] I.C. Gelissen, M. Harris, K.A. Rye, C. Quinn, A.J. Brown, M. Kockx, S. Cartland, M. Packianathan, L. Kritharides, W. Jessup, ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I, Arterioscler. Thromb. Vasc. Biol. 26 (2006) 534–540. [21] M.L. Fitzgerald, A.J. Mendez, K.J. Moore, L.P. Andersson, H.A. Panjeton, M.W. Freeman, ATP-binding cassette transporter A1 contains an NH2-terminal signal anchor sequence that translocates the protein's first hydrophilic domain to the exoplasmic space, J. Biol. Chem. 276 (2001) 15137–15145. [22] A.D. Attie, ABCA1: at the nexus of cholesterol, HDL and atherosclerosis, Trends Biochem. Sci. 32 (2007) 172–179. [23] E.B. Neufeld, A.T. Remaley, S.J. Demosky, J.A. Stonik, A.M. Cooney, M. Comly, N.K. Dwyer, M. Zhang, J. Blanchette-Mackie, S. Santamarina-Fojo, H.B. Brewer Jr., Cellular localization and trafficking of the human ABCA1 transporter, J. Biol. Chem. 276 (2001) 27584–27590. [24] E.B. Neufeld, J.A. Stonik, S.J. Demosky Jr., C.L. Knapper, C.A. Combs, A. Cooney, M. Comly, N. Dwyer, J. Blanchette-Mackie, A.T. Remaley, S. Santamarina-Fojo, H.B. Brewer Jr., The ABCA1 transporter modulates late endocytic trafficking: insights from the correction of the genetic defect in Tangier disease, J. Biol. Chem. 279 (2004) 15571–15578.

569

[25] W. Chen, N. Wang, A.R. Tall, A PEST deletion mutant of ABCA1 shows impaired internalization and defective cholesterol efflux from late endosomes, J. Biol. Chem. 280 (2005) 29277–29281. [26] M. Denis, Y.D. Landry, X. Zha, ATP-binding cassette A1-mediated lipidation of apolipoprotein A-I occurs at the plasma membrane and not in the endocytic compartments, J. Biol. Chem. 283 (2008) 16178–16186. [27] L.E. Faulkner, S.E. Panagotopulos, J.D. Johnson, L.A. Woollett, D.Y. Hui, S.R. Witting, J.N. Maiorano, W.S. Davidson, An analysis of the role of a retroendocytosis pathway in ABCA1-mediated cholesterol efflux from macrophages, J. Lipid Res. 49 (2008) 1322–1332. [28] R. Lu, R. Arakawa, C. Ito-Osumi, N. Iwamoto, S. Yokoyama, ApoA-I facilitates ABCA1 recycle/accumulation to cell surface by inhibiting its intracellular degradation and increases HDL generation, Arterioscler. Thromb. Vasc. Biol. 28 (2008) 1820–1824. [29] M. Denis, B. Haidar, M. Marcil, M. Bouvier, L. Krimbou, J. Genest, Characterization of oligomeric human ATP binding cassette transporter A1. Potential implications for determining the structure of nascent high density lipoprotein particles, J. Biol. Chem. 279 (2004) 41529–41536. [30] D. Trompier, M. Alibert, S. Davanture, Y. Hamon, M. Pierres, G. Chimini, Transition from dimers to higher oligomeric forms occurs during the ATPase cycle of the ABCA1 transporter, J. Biol. Chem. (2006). [31] A.M. Vaughan, J.F. Oram, ABCA1 redistributes membrane cholesterol independent of apolipoprotein interactions, J. Lipid. Res. 44 (2003) 1373–1380. [32] N. Wang, D.L. Silver, C. Thiele, A.R. Tall, ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein, J. Biol. Chem. 276 (2001) 23742–23747. [33] P.E. Fielding, K. Nagao, H. Hakamata, G. Chimini, C.J. Fielding, A two-step mechanism for free cholesterol and phospholipid efflux from human vascular cells to apolipoprotein A-1, Biochemistry 39 (2000) 14113–14120. [34] L. Liu, A.E. Bortnick, M. Nickel, P. Dhanasekaran, P.V. Subbaiah, S. Lund-Katz, G.H. Rothblat, M.C. Phillips, Effects of apolipoprotein A-I on ATP-binding cassette transporter A1-mediated efflux of macrophage phospholipid and cholesterol: formation of nascent high density lipoprotein particles, J. Biol. Chem. 278 (2003) 42976–42984. [35] O. Chambenoit, Y. Hamon, D. Marguet, H. Rigneault, M. Rosseneu, G. Chimini, Specific docking of apolipoprotein A-I at the cell surface requires a functional ABCA1 transporter, J. Biol. Chem. 276 (2001) 9955–9960. [36] Y. Hamon, C. Broccardo, O. Chambenoit, M.F. Luciani, F. Toti, S. Chaslin, J.M. Freyssinet, P.F. Devaux, J. McNeish, D. Marguet, G. Chimini, ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine, Nat. Cell Biol. 2 (2000) 399–406. [37] V. Combes, N. Coltel, M. Alibert, M. van Eck, C. Raymond, I. Juhan-Vague, G.E. Grau, G. Chimini, ABCA1 gene deletion protects against cerebral malaria: potential pathogenic role of microparticles in neuropathology, Am. J. Pathol. 166 (2005) 295–302. [38] S. Nandi, L. Ma, M. Denis, J. Karwatsky, Z. Li, X.C. Jiang, X. Zha, ABCA1-mediated cholesterol efflux generates microparticles in addition to HDL through processes governed by membrane rigidity, J. Lipid Res. (2008). [39] P.T. Duong, H.L. Collins, M. Nickel, S. Lund-Katz, G.H. Rothblat, M.C. Phillips, Characterization of nascent HDL particles and microparticles formed by ABCA1mediated efflux of cellular lipids to apoA-I, J. Lipid Res. 47 (2006) 832–843. [40] J.F. Oram, A.M. Vaughan, R. Stocker, ATP-binding cassette transporter A1 mediates cellular secretion of alpha-tocopherol, J. Biol. Chem. 276 (2001) 39898–39902. [41] A. Von Eckardstein, C. Langer, T. Engel, I. Schaukal, A. Cignarella, J. Reinhardt, S. Lorkowski, Z. Li, X. Zhou, P. Cullen, G. Assmann, ATP binding cassette transporter ABCA1 modulates the secretion of apolipoprotein E from human monocytederived macrophages, FASEB J. 15 (2001) 1555–1561. [42] X. Zhou, T. Engel, C. Goepfert, M. Erren, G. Assmann, A. von Eckardstein, The ATP binding cassette transporter A1 contributes to the secretion of interleukin 1beta from macrophages but not from monocytes, Biochem. Biophys. Res. Commun. 291 (2002) 598–604. [43] Y. Hamon, M.F. Luciani, F. Becq, B. Verrier, A. Rubartelli, G. Chimini, Interleukin1beta secretion is impaired by inhibitors of the Atp binding cassette transporter, ABC1, Blood 90 (1997) 2911–2915. [44] P.T. Duong, G.L. Weibel, S. Lund-Katz, G.H. Rothblat, M.C. Phillips, Characterization and properties of pre beta-HDL particles formed by ABCA1-mediated cellular lipid efflux to apoA-I, J. Lipid Res. 49 (2008) 1006–1014. [45] A. Mulya, J.Y. Lee, A.K. Gebre, M.J. Thomas, P.L. Colvin, J.S. Parks, Minimal lipidation of pre-beta HDL by ABCA1 results in reduced ability to interact with ABCA1, Arterioscler. Thromb. Vasc. Biol. 27 (2007) 1828–1836. [46] A.T. Remaley, J.A. Stonik, S.J. Demosky, E.B. Neufeld, A.V. Bocharov, T.G. Vishnyakova, T.L. Eggerman, A.P. Patterson, N.J. Duverger, S. Santamarina-Fojo, H.B. Brewer Jr., Apolipoprotein specificity for lipid efflux by the human ABCAI transporter, Biochem. Biophys. Res. Commun. 280 (2001) 818–823. [47] J.P. Segrest, M.K. Jones, H. De Loof, C.G. Brouillette, Y.V. Venkatachalapathi, G.M. Anantharamaiah, The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function, J. Lipid Res. 33 (1992) 141–166. [48] A.J. Mendez, G.M. Anantharamaiah, J.P. Segrest, J.F. Oram, Synthetic amphipathic helical peptides that mimic apolipoprotein A-I in clearing cellular cholesterol, J. Clin. Invest. 94 (1994) 1698–1705. [49] A.T. Remaley, F. Thomas, J.A. Stonik, S.J. Demosky, S.E. Bark, E.B. Neufeld, A.V. Bocharov, T.G. Vishnyakova, A.P. Patterson, T.L. Eggerman, S. Santamarina-Fojo, H.B. Brewer, Synthetic amphipathic helical peptides promote lipid efflux from cells by an ABCA1-dependent and an ABCA1-independent pathway, J. Lipid Res. 44 (2003) 828–836.

570

C. Tang, J.F. Oram / Biochimica et Biophysica Acta 1791 (2009) 563–572

[50] C. Tang, A.M. Vaughan, G.M. Anantharamaiah, J.F. Oram, Janus kinase 2 modulates the lipid-removing but not protein-stabilizing interactions of amphipathic helices with ABCA1, J. Lipid Res. 47 (2006) 107–114. [51] P.G. Yancey, J.K. Bielicki, W.J. Johnson, S. Lund-Katz, M.N. Palgunachari, G.M. Anantharamaiah, J.P. Segrest, M.C. Phillips, G.H. Rothblat, Efflux of cellular cholesterol and phospholipid to lipid-free apolipoproteins and class A amphipathic peptides, Biochemistry 34 (1995) 7955–7965. [52] R. Arakawa, S. Yokoyama, Helical apolipoproteins stabilize ATP-binding cassette transporter A1 by protecting it from thiol protease-mediated degradation, J. Biol. Chem. 277 (2002) 22426–22429. [53] J.F. Oram, G. Wolfbauer, A.M. Vaughan, C. Tang, J.J. Albers, Phospholipid transfer protein interacts with and stabilizes ATP-binding cassette transporter A1 and enhances cholesterol efflux from cells, J. Biol. Chem. 278 (2003) 52379–52385. [54] J.F. Oram, G. Wolfbauer, C. Tang, W.S. Davidson, J.J. Albers, An amphipathic helical region of the N-terminal barrel of phospholipid transfer protein is critical for ABCA1-dependent cholesterol efflux, J. Biol. Chem. 283 (2008) 11541–11549. [55] J.A. Stonik, A.T. Remaley, S.J. Demosky, E.B. Neufeld, A. Bocharov, H.B. Brewer, Serum amyloid A promotes ABCA1-dependent and ABCA1-independent lipid efflux from cells, Biochem. Biophys. Res. Commun. 321 (2004) 936–941. [56] J.S. Hoffman, E.P. Benditt, Changes in high density lipoprotein content following endotoxin administration in the mouse. Formation of serum amyloid proteinrich subfractions, J. Biol. Chem. 257 (1982) 10510–10517. [57] T. Langmann, J. Klucken, M. Reil, G. Liebisch, M.F. Luciani, G. Chimini, W.E. Kaminski, G. Schmitz, Molecular cloning of the human ATP-binding cassette transporter 1 (hABC1): evidence for sterol-dependent regulation in macrophages, Biochem. Biophys. Res. Commun. 257 (1999) 29–33. [58] R.M. Lawn, D.P. Wade, M.R. Garvin, X. Wang, K. Schwartz, J.G. Porter, J.J. Seilhamer, A.M. Vaughan, J.F. Oram, The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway, J. Clin. Invest. 104 (1999) R25–31. [59] K. Schwartz, R.M. Lawn, D.P. Wade, ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR, Biochem. Biophys. Res. Commun. 274 (2000) 794–802. [60] P. Costet, Y. Luo, N. Wang, A.R. Tall, Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor, J. Biol. Chem. 275 (2000) 28240–28245. [61] J.J. Repa, D.J. Mangelsdorf, Nuclear receptor regulation of cholesterol and bile acid metabolism, Curr. Opin. Biotechnol. 10 (1999) 557–563. [62] B.A. Janowski, M.J. Grogan, S.A. Jones, G.B. Wisely, S.A. Kliewer, E.J. Corey, D.J. Mangelsdorf, Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta, Proc. Natl. Acad. Sci. U. S. A. 96 (1999) 266–271. [63] X. Fu, J.G. Menke, Y. Chen, G. Zhou, K.L. MacNaul, S.D. Wright, C.P. Sparrow, E.G. Lund, 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells, J. Biol. Chem. 276 (2001) 38378–38387. [64] C.L. Wellington, E.K. Walker, A. Suarez, A. Kwok, N. Bissada, R. Singaraja, Y.Z. Yang, L.H. Zhang, E. James, J.E. Wilson, O. Francone, B.M. McManus, M.R. Hayden, ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation, Lab. Invest. 82 (2002) 273–283. [65] J.F. Oram, R.M. Lawn, M.R. Garvin, D.P. Wade, ABCA1 is the cAMP-inducible apolipoprotein receptor that mediates cholesterol secretion from macrophages, J. Biol. Chem. 275 (2000) 34508–34511. [66] N. Wang, W. Chen, P. Linsel-Nitschke, L.O. Martinez, B. Agerholm-Larsen, D.L. Silver, A.R. Tall, A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I, J. Clin. Invest. 111 (2003) 99–107. [67] Y. Wang, J.F. Oram, Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increasing degradation of ATP-binding cassette transporter A1, J. Biol. Chem. 277 (2002) 5692–5697. [68] M.L. Alfaro Leon, G.F. Evans, M.W. Farmen, S.H. Zuckerman, Post-transcriptional regulation of macrophage ABCA1, an early response gene to IFN-gamma, Biochem. Biophys. Res. Commun. 333 (2005) 596–602. [69] Y. Wang, B. Kurdi-Haidar, J.F. Oram, LXR-mediated activation of macrophage stearoyl-CoA desaturase generates unsaturated fatty acids that destabilize ABCA1, J. Lipid Res. 45 (2004) 972–980. [70] Y. Wang, J.F. Oram, Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a phospholipase D2 pathway, J. Biol. Chem. 280 (2005) 35896–35903. [71] Y. Wang, J.F. Oram, Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a protein kinase C delta pathway, J. Lipid Res. 48 (2007) 1062–1068. [72] A. Chroni, T. Liu, M.L. Fitzgerald, M.W. Freeman, V.I. Zannis, Cross-linking and lipid efflux properties of apoA-I mutants suggest direct association between apoA-I helices and ABCA1, Biochemistry 43 (2004) 2126–2139. [73] M.L. Fitzgerald, A.L. Morris, A. Chroni, A.J. Mendez, V.I. Zannis, M.W. Freeman, ABCA1 and amphipathic apolipoproteins form high-affinity molecular complexes required for cholesterol efflux, J. Lipid Res. 45 (2004) 287–294. [74] C. Tang, A.M. Vaughan, J.F. Oram, Janus kinase 2 modulates the apolipoprotein interactions with ABCA1 required for removing cellular cholesterol, J. Biol. Chem. 279 (2005) 7622–7628. [75] Y. Yamauchi, M. Hayashi, S. Abe-Dohmae, S. Yokoyama, ApoA-I activates PKCalpha signaling to phosphorylate and stabilize ABCA1 for the HDL assemblym, J. Biol. Chem. (On line) (in press). [76] J.R. Nofer, A.T. Remaley, R. Feuerborn, I. Wolinnska, T. Engel, A. von Eckardstein, G. Assmann, Apolipoprotein A-I activates Cdc42 signaling through the ABCA1 transporter, J. Lipid Res. 47 (2006) 794–803. [77] I.M. Kerr, A.P. Costa-Pereira, B.F. Lillemeier, B. Strobl, Of JAKs, STATs, blind watchmakers, jeeps and trains, FEBS Lett. 546 (2003) 1–5.

[78] A.M. Vaughan, C. Tang, J.F. Oram, ABCA1 mutants reveal an interdependency between lipid export function, apoA-I binding activity, and Janus kinase 2 activation, J. Lipid Res. 50 (2009) 285–292. [79] C. Tang, J.F. Oram, ApoA-I activates both JAK2 and STAT3 through ABCA1, but only JAK2 regulates cholesterol export from cells, Arterioscler. Thromb. Vasc. Biol. 26 (2006) e56. [80] X. Zhu, J.Y. Lee, J.M. Timmins, J.M. Brown, E. Boudyguina, A. Mulya, A.K. Gebre, M.C. Willingham, E.M. Hiltbold, N. Mishra, N. Maeda, J.S. Parks, Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances proinflammatory response of macrophages, J. Biol. Chem. 283 (2008) 22930–22941. [81] M. Koseki, K. Hirano, D. Masuda, C. Ikegami, M. Tanaka, A. Ota, J.C. Sandoval, Y. Nakagawa-Toyama, S.B. Sato, T. Kobayashi, Y. Shimada, Y. Ohno-Iwashita, F. Matsuura, I. Shimomura, S. Yamashita, Increased lipid rafts and accelerated lipopolysaccharide-induced tumor necrosis factor-alpha secretion in Abca1deficient macrophages, J. Lipid Res. 48 (2007) 299–306. [82] Z. Wolf, E. Orso, T. Werner, H.H. Klunemann, G. Schmitz, Monocyte cholesterol homeostasis correlates with the presence of detergent resistant membrane microdomains, Cytometry A 71 (2007) 486–494. [83] L. Yvan-Charvet, C. Welch, T.A. Pagler, M. Ranalletta, M. Lamkanfi, S. Han, M. Ishibashi, R. Li, N. Wang, A.R. Tall, Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signaling via toll-like receptors, and neutrophil infiltration of atherosclerotic lesions, Circulation 118 (2008) 1837–1847. [84] A.J. Murphy, K.J. Woollard, A. Hoang, N. Mukhamedova, R.A. Stirzaker, S.P. McCormick, A.T. Remaley, D. Sviridov, J. Chin-Dusting, High-density lipoprotein reduces the human monocyte inflammatory response, Arterioscler. Thromb. Vasc. Biol. 28 (2008) 2071–2077. [85] E. Tellier, M. Canault, M. Poggi, B. Bonardo, A. Nicolay, M.C. Alessi, G. Nalbone, F. Peiretti, HDLs activate ADAM17-dependent shedding, J. Cell. Physiol. 214 (2008) 687–693. [86] L.M. Williams, U. Sarma, K. Willets, T. Smallie, F. Brennan, B.M. Foxwell, Expression of constitutively active STAT3 can replicate the cytokine-suppressive activity of interleukin-10 in human primary macrophages, J. Biol. Chem. 282 (2007) 6965–6975. [87] P.J. Murray, Understanding and exploiting the endogenous interleukin-10/ STAT3-mediated anti-inflammatory response, Curr. Opin. Pharmacol. 6 (2006) 379–386. [88] D.E. Levy, C.K. Lee, What does Stat3 do? J. Clin. Invest. 109 (2002) 1143–1148. [89] M.F. Rosenberg, R. Callaghan, R.C. Ford, C.F. Higgins, Structure of the multidrug resistance P-glycoprotein to 2.5 nm resolution determined by electron microscopy and image analysis, J. Biol. Chem. 272 (1997) 10685–10694. [90] A. Ward, C.L. Reyes, J. Yu, C.B. Roth, G. Chang, Flexibility in the ABC transporter MsbA: alternating access with a twist, Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 19005–19010. [91] R.J. Dawson, K.P. Locher, Structure of a bacterial multidrug ABC transporter, Nature 443 (2006) 180–185. [92] G. Lin, J.F. Oram, Apolipoprotein binding to protruding membrane domains during removal of excess cellular cholesterol, Atherosclerosis 149 (2000) 359–370. [93] C. Vedhachalam, P.T. Duong, M. Nickel, D. Nguyen, P. Dhanasekaran, H. Saito, G.H. Rothblat, S. Lund-Katz, M.C. Phillips, 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. 282 (2007) 25123–25130. [94] H.H. Hassan, M. Denis, D.Y. Lee, I. Iatan, D. Nyholt, I. Ruel, L. Krimbou, J. Genest, Identification of an ABCA1-dependent phospholipid-rich plasma membrane apolipoprotein A-I binding site for nascent HDL formation: implications for current models of HDL biogenesis, J. Lipid Res. 48 (2007) 2428–2442. [95] C. Vedhachalam, A.B. Ghering, W.S. Davidson, S. Lund-Katz, G.H. Rothblat, M.C. Phillips, ABCA1-induced cell surface binding sites for ApoA-I, Arterioscler. Thromb. Vasc. Biol. 27 (2007) 1603–1609. [96] R.R. Singaraja, L.R. Brunham, H. Visscher, J.J. Kastelein, M.R. Hayden, Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene, Arterioscler. Thromb. Vasc. Biol. 23 (2003) 1322–1332. [97] J.C. Cohen, R.S. Kiss, A. Pertsemlidis, Y.L. Marcel, R. McPherson, H.H. Hobbs, Multiple rare alleles contribute to low plasma levels of HDL cholesterol, Science 305 (2004) 869–872. [98] R. Frikke-Schmidt, B.G. Nordestgaard, G.B. Jensen, A. Tybjaerg-Hansen, Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population, J. Clin. Invest. 114 (2004) 1343–1353. [99] L.R. Brunham, R.R. Singaraja, M.R. Hayden, Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis, Annu. Rev. Nutr. (2006). [100] S.M. Clee, J.J. Kastelein, M. van Dam, M. Marcil, K. Roomp, K.Y. Zwarts, J.A. Collins, R. Roelants, N. Tamasawa, T. Stulc, T. Suda, R. Ceska, B. Boucher, C. Rondeau, C. DeSouich, A. Brooks-Wilson, H.O. Molhuizen, J. Frohlich, J. Genest Jr., M.R. Hayden, Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes, J. Clin. Invest. 106 (2000) 1263–1270. [101] R.R. Singaraja, H. Visscher, E.R. James, A. Chroni, J.M. Coutinho, L.R. Brunham, M.H. Kang, V.I. Zannis, G. Chimini, M.R. Hayden, Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro, Circ. Res. 99 (2006) 389–397. [102] M.J. van Dam, E. de Groot, S.M. Clee, G.K. Hovingh, R. Roelants, A. Brooks-Wilson, A.H. Zwinderman, A.J. Smit, A.H. Smelt, A.K. Groen, M.R. Hayden, J.J. Kastelein, Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study, Lancet 359 (2002) 37–42.

C. Tang, J.F. Oram / Biochimica et Biophysica Acta 1791 (2009) 563–572 [103] R.J. Aiello, D. Brees, O.L. Francone, ABCA1-deficient mice: insights into the role of monocyte lipid efflux in HDL formation and inflammation, Arterioscler. Thromb. Vasc. Biol. 23 (2003) 972–980. [104] C. Joyce, L. Freeman, H.B. Brewer Jr., S. Santamarina-Fojo, Study of ABCA1 function in transgenic mice, Arterioscler. Thromb. Vasc. Biol. 23 (2003) 965–971. [105] C.L. Wellington, L.R. Brunham, S. Zhou, R.R. Singaraja, H. Visscher, A. Gelfer, C. Ross, E. James, G. Liu, M.T. Huber, Y.Z. Yang, R.J. Parks, A. Groen, J. Fruchart-Najib, M.R. Hayden, Alterations of plasma lipids in mice via adenoviral-mediated hepatic overexpression of human ABCA1, J. Lipid Res. 44 (2003) 1470–1480. [106] R.R. Singaraja, C. Fievet, G. Castro, E.R. James, N. Hennuyer, S.M. Clee, N. Bissada, J.C. Choy, J.C. Fruchart, B.M. McManus, B. Staels, M.R. Hayden, Increased ABCA1 activity protects against atherosclerosis, J. Clin. Invest. 110 (2002) 35–42. [107] C.L. Wellington, L.R. Brunham, S. Zhou, R.R. Singaraja, H. Visscher, A. Gelfer, C. Ross, E. James, G. Liu, M.T. Huber, Y.Z. Yang, R.J. Parks, A. Groen, J. Fruchart-Najib, M.R. Hayden, Alterations of plasma lipids in mice via adenoviral mediated hepatic overexpression of human ABCA1, J. Lipid Res. (2003). [108] J.Y. Lee, J.S. Parks, ATP-binding cassette transporter AI and its role in HDL formation, Curr. Opin. Lipidol. 16 (2005) 19–25. [109] L.R. Brunham, J.K. Kruit, J. Iqbal, C. Fievet, J.M. Timmins, T.D. Pape, B.A. Coburn, N. Bissada, B. Staels, A.K. Groen, M.M. Hussain, J.S. Parks, F. Kuipers, M.R. Hayden, Intestinal ABCA1 directly contributes to HDL biogenesis in vivo, J. Clin. Invest. 116 (2006) 1052–1062. [110] J.M. Timmins, J.Y. Lee, E. Boudyguina, K.D. Kluckman, L.R. Brunham, A. Mulya, A.K. Gebre, J.M. Coutinho, P.L. Colvin, T.L. Smith, M.R. Hayden, N. Maeda, J.S. Parks, Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I, J. Clin. Invest. 115 (2005) 1333–1342. [111] C. Serfaty-Lacrosniere, F. Civeira, A. Lanzberg, P. Isaia, J. Berg, E.D. Janus, M.P. Smith Jr., P.H. Pritchard, J. Frohlich, R.S. Lees, G.F. Barnard, J.M. Ordovas, E.J. Schaefer, Homozygous Tangier disease and cardiovascular disease, Atherosclerosis 107 (1994) 85–98. [112] R. Frikke-Schmidt, B.G. Nordestgaard, G.B. Jensen, R. Steffensen, A. TybjaergHansen, Genetic variation in ABCA1 predicts ischemic heart disease in the general population, Arterioscler. Thromb. Vasc. Biol. 28 (2008) 180–186. [113] R. Frikke-Schmidt, B.G. Nordestgaard, M.C. Stene, A.A. Sethi, A.T. Remaley, P. Schnohr, P. Grande, A. Tybjaerg-Hansen, Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease, JAMA 299 (2008) 2524–2532. [114] S.M. Clee, A.H. Zwinderman, J.C. Engert, K.Y. Zwarts, H.O. Molhuizen, K. Roomp, J.W. Jukema, M. van Wijland, M. van Dam, T.J. Hudson, A. Brooks-Wilson, J. Genest Jr., J.J. Kastelein, M.R. Hayden, Common genetic variation in abca1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease, Circulation 103 (2001) 1198–1205. [115] C.W. Joyce, M.J. Amar, G. Lambert, B.L. Vaisman, B. Paigen, J. Najib-Fruchart, R.F. Hoyt Jr., E.D. Neufeld, A.T. Remaley, D.S. Fredrickson, H.B. Brewer Jr., S. Santamarina-Fojo, The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice, Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 407–412. [116] R.J. Aiello, D. Brees, P.A. Bourassa, L. Royer, S. Lindsey, T. Coskran, M. Haghpassand, O.L. Francone, Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages, Arterioscler. Thromb. Vasc. Biol. 22 (2002) 630–637. [117] M. van Eck, I.S. Bos, W.E. Kaminski, E. Orso, G. Rothe, J. Twisk, A. Bottcher, E.S. Van Amersfoort, T.A. Christiansen-Weber, W.P. Fung-Leung, T.J. Van Berkel, G. Schmitz, Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues, Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 6298–6303. [118] M. Van Eck, R.R. Singaraja, D. Ye, R.B. Hildebrand, E.R. James, M.R. Hayden, T.J. Van Berkel, Macrophage ATP-binding cassette transporter A1 overexpression inhibits atherosclerotic lesion progression in low-density lipoprotein receptor knockout mice, Arterioscler. Thromb. Vasc. Biol. 26 (2006) 929–934. [119] L.R. Brunham, J.K. Kruit, C.B. Verchere, M.R. Hayden, Cholesterol in islet dysfunction and type 2 diabetes, J. Clin. Invest. 118 (2008) 403–408. [120] L.R. Brunham, J.K. Kruit, T.D. Pape, J.M. Timmins, A.Q. Reuwer, Z. Vasanji, B.J. Marsh, B. Rodrigues, J.D. Johnson, J.S. Parks, C.B. Verchere, M.R. Hayden, Beta-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment, Nat. Med. 13 (2007) 340–347. [121] H.C. Gerstein, S. Yusuf, J. Bosch, J. Pogue, P. Sheridan, N. Dinccag, M. Hanefeld, B. Hoogwerf, M. Laakso, V. Mohan, J. Shaw, B. Zinman, R.R. Holman, Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial, Lancet 368 (2006) 1096–1105. [122] J.M. Lehmann, L.B. Moore, T.A. Smith-Oliver, W.O. Wilkison, T.M. Willson, S.A. Kliewer, An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma), J. Biol. Chem. 270 (1995) 12953–12956. [123] A. Chawla, W.A. Boisvert, C.H. Lee, B.A. Laffitte, Y. Barak, S.B. Joseph, D. Liao, L. Nagy, P.A. Edwards, L.K. Curtiss, R.M. Evans, P. Tontonoz, A PPAR gamma-LXRABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis, Mol. Cell 7 (2001) 161–171. [124] G. Chinetti, S. Lestavel, V. Bocher, A.T. Remaley, B. Neve, I.P. Torra, E. Teissier, A. Minnich, M. Jaye, N. Duverger, H.B. Brewer, J.C. Fruchart, V. Clavey, B. Staels, PPARalpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway, Nat. Med. 7 (2001) 53–58. [125] M.T. Villarreal-Molina, C.A. Aguilar-Salinas, M. Rodriguez-Cruz, D. Riano, M. Villalobos-Comparan, R. Coral-Vazquez, M. Menjivar, P. Yescas-Gomez, M. Konigsoerg-Fainstein, S. Romero-Hidalgo, M.T. Tusie-Luna, S. Canizales-Quinteros, The

[126]

[127]

[128]

[129] [130] [131]

[132] [133] [134]

[135]

[136] [137]

[138]

[139]

[140] [141]

[142]

[143] [144]

[145]

[146]

[147]

[148]

[149]

[150] [151]

[152]

[153]

571

ATP-binding cassette transporter A1 R230C variant affects HDL cholesterol levels and BMI in the Mexican population: association with obesity and obesity-related comorbidities, Diabetes 56 (2007) 1881–1887. M.T. Villarreal-Molina, M.T. Flores-Dorantes, O. Arellano-Campos, M. VillalobosComparan, M. Rodriguez-Cruz, A. Miliar-Garcia, A. Huertas-Vazquez, M. Menjivar, S. Romero-Hidalgo, N.H. Wacher, M.T. Tusie-Luna, M. Cruz, C.A. Aguilar-Salinas, S. Canizales-Quinteros, Association of the ATP-binding cassette transporter A1 R230C variant with early-onset type 2 diabetes in a Mexican population, Diabetes 57 (2008) 509–513. S.B. Harris, J. Gittelsohn, A. Hanley, A. Barnie, T.M. Wolever, J. Gao, A. Logan, B. Zinman, The prevalence of NIDDM and associated risk factors in native Canadians, Diabetes Care 20 (1997) 185–187. C.A. Salinas, I. Cruz-Bautista, R. Mehta, M.T. Villarreal-Molina, F.J. Perez, M.T. Tusie-Luna, S. Canizales-Quinteros, The ATP-binding cassette transporter subfamily A member 1 (ABC-A1) and type 2 diabetes: an association beyond HDL cholesterol, Curr. Diabetes Rev. 3 (2007) 264–267. E.L. Bierman, George Lyman Duff Memorial Lecture. Atherogenesis in diabetes, Arterioscler. Thromb. 12 (1992) 647–656. W.B. Kannel, D.L. McGee, Diabetes and cardiovascular risk factors: the Framingham study, Circulation 59 (1979) 8–13. D.M. Nathan, J. Lachin, P. Cleary, T. Orchard, D.J. Brillon, J.Y. Backlund, D.H. O'Leary, S. Genuth, Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus, N. Engl. J. Med. 348 (2003) 2294–2303. N.B. Ruderman, J.R. Williamson, M. Brownlee, Glucose and diabetic vascular disease, FASEB J. 6 (1992) 2905–2914. H.N. Ginsberg, Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis, Diabetes Care 14 (1991) 839–855. J.M. Hayden, P.D. Reaven, Cardiovascular disease in diabetes mellitus type 2: a potential role for novel cardiovascular risk factors, Curr. Opin. Lipidol. 11 (2000) 519–528. P. Zimmet, D. Magliano, Y. Matsuzawa, G. Alberti, J. Shaw, The metabolic syndrome: a global public health problem and a new definition, J. Atheroscler. Thromb. 12 (2005) 295–300. S.M. Haffner, Risk constellations in patients with the metabolic syndrome: epidemiology, diagnosis, and treatment patterns, Am. J. Med. 119 (2006) S3–S9. A.J. Jenkins, T.J. Lyons, D. Zheng, J.D. Otvos, D.T. Lackland, D. McGee, W.T. Garvey, R.L. Klein, Serum lipoproteins in the diabetes control and complications trial/ epidemiology of diabetes intervention and complications cohort: associations with gender and glycemia, Diabetes Care 26 (2003) 810–818. G.M. Reaven, C. Hollenbeck, C.Y. Jeng, M.S. Wu, Y.D. Chen, Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM, Diabetes 37 (1988) 1020–1024. M. Seigneur, G. Freyburger, H. Gin, M. Claverie, D. Lardeau, G. Lacape, F. Le Moigne, R. Crockett, M.R. Boisseau, Serum fatty acid profiles in type I and type II diabetes: metabolic alterations of fatty acids of the main serum lipids, Diabetes Res. Clin. Pract. 23 (1994) 169–177. J.W. Baynes, S.R. Thorpe, Glycoxidation and lipoxidation in atherogenesis, Free Radic. Biol. Med. 28 (2000) 1708–1716. M. Brownlee, A. Cerami, H. Vlassara, Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications, N. Engl. J. Med. 318 (1988) 1315–1321. P.J. Thornalley, A. Langborg, H.S. Minhas, Formation of glyoxal, methylglyoxal and 3-deoxyglucosone in the glycation of proteins by glucose, Biochem. J. 344 (Pt 1) (1999) 109–116. M. Passarelli, J.F. Oram, Cellular glycoxidation impairs the ABCA1-mediated lipid secretory pathway, Circulation 102 (2000) II–312. M. Passarelli, C. Tang, T.O. McDonald, K.D. O'Brien, R.G. Gerrity, J.W. Heinecke, J.F. Oram, Advanced glycation end product precursors impair ABCA1-dependent cholesterol removal from cells, Diabetes 54 (2005) 2198–2205. C. Tang, T. McMillen, J.E. Kanter, K.E. Bornfeldt, R.C. LeBoeuf, J.F. Oram, Expression of ABCA1 is selectively impaired in macrophages and kidneys in diabetic mice, Arterioscler. Thromb. Vasc. Biol. 25 (2005) e93. B.A. Laffitte, J.J. Repa, S.B. Joseph, D.C. Wilpitz, H.R. Kast, D.J. Mangelsdorf, P. Tontonoz, LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes, Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 507–512. Z.H. Huang, C.Y. Lin, J.F. Oram, T. Mazzone, Sterol efflux mediated by endogenous macrophage ApoE expression is independent of ABCA1, Arterioscler. Thromb. Vasc. Biol. 21 (2001) 2019–2025. J.J. Repa, K.E. Berge, C. Pomajzl, J.A. Richardson, H. Hobbs, D.J. Mangelsdorf, Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta, J. Biol. Chem. 277 (2002) 18793–18800. L. Yu, S. Gupta, F. Xu, A.D. Liverman, A. Moschetta, D.J. Mangelsdorf, J.J. Repa, H.H. Hobbs, J.C. Cohen, Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion, J. Biol. Chem. 280 (2005) 8742–8747. P. Tontonoz, D.J. Mangelsdorf, Liver x receptor signaling pathways in cardiovascular disease, Mol. Endocrinol. 17 (2003) 985–993. S.B. Joseph, E. McKilligin, L. Pei, M.A. Watson, A.R. Collins, B.A. Laffitte, M. Chen, G. Noh, J. Goodman, G.N. Hagger, J. Tran, T.K. Tippin, X. Wang, A.J. Lusis, W.A. Hsueh, R.E. Law, J.L. Collins, T.M. Willson, P. Tontonoz, Synthetic LXR ligand inhibits the development of atherosclerosis in mice, Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 7604–7609. B. Miao, S. Zondlo, S. Gibbs, D. Cromley, V.P. Hosagrahara, T.G. Kirchgessner, J. Billheimer, R. Mukherjee, Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator, J. Lipid Res. 45 (2004) 1410–1417. J.J. Repa, G. Liang, J. Ou, Y. Bashmakov, J.M. Lobaccaro, I. Shimomura, B. Shan, M.S. Brown, J.L. Goldstein, D.J. Mangelsdorf, Regulation of mouse sterol regulatory

572

[154]

[155]

[156]

[157]

[158]

[159]

[160]

C. Tang, J.F. Oram / Biochimica et Biophysica Acta 1791 (2009) 563–572 element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta, Genes Dev. 14 (2000) 2819–2830. J.R. Schultz, H. Tu, A. Luk, J.J. Repa, J.C. Medina, L. Li, S. Schwendner, S. Wang, M. Thoolen, D.J. Mangelsdorf, K.D. Lustig, B. Shan, Role of LXRs in control of lipogenesis, Genes Dev. 14 (2000) 2831–2838. T.F. Osborne, Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action, J. Biol. Chem. 275 (2000) 32379–32382. T. Claudel, M.D. Leibowitz, C. Fievet, A. Tailleux, B. Wagner, J.J. Repa, G. Torpier, J.M. Lobaccaro, J.R. Paterniti, D.J. Mangelsdorf, R.A. Heyman, J. Auwerx, Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor, Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 2610–2615. P. Costet, F. Lalanne, M.C. Gerbod-Giannone, J.R. Molina, X. Fu, E.G. Lund, L.J. Gudas, A.R. Tall, Retinoic acid receptor-mediated induction of ABCA1 in macrophages, Mol. Cell. Biol. 23 (2003) 7756–7766. S.J. Peterson, G. Drummond, D.H. Kim, M. Li, A.L. Kruger, S. Ikehara, N.G. Abraham, L-4F treatment reduces adiposity, increases adiponectin levels, and improves insulin sensitivity in obese mice, J. Lipid Res. 49 (2008) 1658–1669. M. Navab, G.M. Anantharamaiah, S.T. Reddy, S. Hama, G. Hough, V.R. Grijalva, N. Yu, B.J. Ansell, G. Datta, D.W. Garber, A.M. Fogelman, Apolipoprotein A-I mimetic peptides, Arterioscler. Thromb. Vasc. Biol. 25 (2005) 1325–1331. M. Navab, G.M. Anantharamaiah, S. Hama, D.W. Garber, M. Chaddha, G. Hough, R. Lallone, A.M. Fogelman, Oral administration of an Apo A-I mimetic peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol, Circulation 105 (2002) 290–292.

[161] M. Navab, G.M. Anantharamaiah, S.T. Reddy, B.J. Van Lenten, G. Datta, D. Garber, A.M. Fogelman, Human apolipoprotein A-I and A-I mimetic peptides: potential for atherosclerosis reversal, Curr. Opin. Lipidol. 15 (2004) 645–649. [162] H. Gupta, L. Dai, G. Datta, D.W. Garber, H. Grenett, Y. Li, V. Mishra, M.N. Palgunachari, S. Handattu, S.H. Gianturco, W.A. Bradley, G.M. Anantharamaiah, C. R. White, Inhibition of lipopolysaccharide-induced inflammatory responses by an apolipoprotein AI mimetic peptide, Circ. Res. 97 (2005) 236–243. [163] J. Ou, J. Wang, H. Xu, Z. Ou, M.G. Sorci-Thomas, D.W. Jones, P. Signorino, J.C. Densmore, S. Kaul, K.T. Oldham, K.A. Pritchard Jr., Effects of D-4F on vasodilation and vessel wall thickness in hypercholesterolemic LDL receptor-null and LDL receptor/apolipoprotein A-I double-knockout mice on Western diet, Circ. Res. 97 (2005) 1190–1197. [164] B. Shao, M.N. Oda, J.F. Oram, J.W. Heinecke, Myeloperoxidase: an inflammatory enzyme for generating dysfunctional high density lipoprotein, Curr. Opin. Cardiol. 21 (2006) 322–328. [165] L. Zheng, B. Nukuna, M.L. Brennan, M. Sun, M. Goormastic, M. Settle, D. Schmitt, X. Fu, L. Thomson, P.L. Fox, H. Ischiropoulos, J.D. Smith, M. Kinter, S.L. Hazen, Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease, J. Clin. Invest. 114 (2004) 529–541. [166] A.A. Sethi, J.A. Stonik, F. Thomas, S.J. Demosky, M. Amar, E. Neufeld, H.B. Brewer, W.S. Davidson, W. D'Souza, D. Sviridov, A.T. Remaley, Asymmetry in the lipid affinity of bihelical amphipathic peptides. A structural determinant for the specificity of ABCA1-dependent cholesterol efflux by peptides, J. Biol. Chem. 283 (2008) 32273–32282.