MINIREVIEW Function and regulation of ABCA1 – membrane meso-domain organization and reorganization Kohjiro Nagao, Maiko Tomioka and Kazumitsu Ueda Institute for Integrated Cell–Material Sciences (iCeMS), Kyoto University, Japan Introduction The plasma membrane is critical for the life of the cell, not only as the boundary maintaining the cytosolic environment differently from the extracellular environ- ment, but also as a platform for protein assembly, which converts extracellular stimuli into intracellular signals. The skin lipid barrier prevents water loss from our body, lipids in the myelin sheath functions as an insulator of nerve fibers, and pulmonary surfactant lip- ids at the air–water interface decrease alveolar surface tension. These lipids are appropriately transported in our body and within cells, and their abnormal deposi- tion causes cell death and various diseases (Table 1). Several ATP-binding cassette protein A (ABCA) sub- family proteins are involved in lipid transport between organs and between intracellular compartments (Table 1). Furthermore, recent studies suggest that ABCA1 moves lipids not only between different mem- branes but also within the same membrane to organize and reorganize submicrometre (meso-scale) membrane domains such as lipid rafts. In this review, the function and regulation of ABCA1 are summarized. Cholesterol homeostasis and ABCA1 Cholesterol is a key component of the cell membrane and is required for cell proliferation; however, excess accumulation of cholesterol is toxic to cells and its excess deposition in peripheral tissues causes Keywords ATP-binding cassette protein; cholesterol homeostasis; lipid raft; membranes; phospholipids Correspondence K. Ueda, Institute for integrated Cell–Material Sciences (iCeMS), Kyoto University, Kyoto 606-8502, Japan Fax: 81 75 753 6104 Tel: 81 75 753 6124 E-mail: uedak@kais.kyoto-u.ac.jp (Received 17 December 2010, revised 27 February 2011, accepted 6 May 2011) doi:10.1111/j.1742-4658.2011.08170.x The ATP-binding cassette protein A1 (ABCA1) mediates the secretion of cellular-free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein A-I, to form high-density lipoprotein. Because ABCA1 is a key factor in cholesterol homeostasis, elaborate transcriptional and post- transcriptional regulations of ABCA1 have evolved to maintain cholesterol homeostasis. Recent studies suggest that ABCA1 moves lipids not only between membranes but also within membranes to organize and reorganize membrane meso-domains to modulate cell proliferation and immunity. Abbreviations ABCA1, ATP-binding cassette protein A1; apoA-I, apolipoprotein A-I; CK2, casein kinase 2; ECD, extracellular domain; HDL, high-density lipoprotein; JAK2, Janus kinase 2; LXR, liver X receptor; LXRE, liver X response element; MbCD, methyl-b-cyclodextrin; NBD, nucleotide binding domain; PC, phosphatidylcholine; PKA, protein kinase A; PKC, protein kinase C; PS, phosphatidylserine; RXR, retinoid X receptor; SM, sphingomyelin; SREBP-2, sterol regulatory element binding protein 2. 3190 FEBS Journal 278 (2011) 3190–3203 ª 2011 The Authors Journal compilation ª 2011 FEBS atherosclerosis. Excess cholesterol in peripheral tissues is reversely transported as high-density lipoprotein (HDL) to the liver. Because cholesterol is not catabo- lized in peripheral tissues, HDL formation is the only pathway by which excess cholesterol is removed from peripheral cells. The inverse relationship between plasma HDL levels and the risk of coronary artery dis- ease is demonstrated [1], although genetically low HDL per se may not predict the increased risk [2]. At least 70 mutations have been identified in the ABCA1 gene, leading to Tangier disease and familial hypoal- phalipoproteinaemia, in which patients have a near absence of or decrease in circulating HDL [3–8] (Fig. 1). More than 15 mutations examined show high correlations between phospholipids, preferentially phosphatidylcholine (PC) and cholesterol efflux [9–11], indicating that ABCA1 influences the efflux of both PC and free cholesterol. Indeed, ABCA1, expressed in cultured cells, mediates the secretion of both types of lipids when lipid-free apolipoprotein A-I (apoA-I), an Table 1. Possible substrates, localization and related diseases of ABCA subfamily proteins. PE, phosphatidylethanolamine; PG, phosphatidyl- glycerol. Possible substrates Subcellular localization Tissue localization Related diseases ABCA1 (similarity with ABCA1) PS [81] PC and cholesterol [54] Oxysterols [105] Cell surface, intracellular vesicles [11,31] Macrophages, liver, small intestine, brain [5,106–108] Tangier’s disease, atherosclerosis [5–7,13] ABCA2 (59.2%) SM, gangliosides [109] Endosome [110] Brain [111,112] Alzheimer’s disease [113–115] ABCA3 (57.3%) PC, PG, PE [116–120] Intracellular vesicles, lamellar bodies [121–123] Lung alveolar type II cells [121,123] Neonatal fatal surfactant deficiency and chronic interstitial lung disease [124,125] ABCA4 (66.7%) All-trans-retinal, N-retinylidene-PE [126–128] Intracellular disc membrane [129] Photoreceptor cells (rod cells, cone cells) [129–131] Stargardt muscular dystrophy, age-related macular degeneration [132–135] ABCA5 (50.3%) Unknown Lysosome, late endosome [136] Brain, lung, heart and thyroid gland [136] Dilated cardiomyopathy [136] ABCA6 (48.6%) Unknown Unknown Unknown Unknown ABCA7 (69.3%) PC, SM, cholesterol [77,79,137] Plasma membrane and intracellular membranes [77,79,137,138] Spleen, lung, adrenal, brain, liver, kidney (proximal tubule), peritoneal macrophages [79,137] Unknown ABCA8 (46.1%) Oestradiol-b-glucuronide, taurocholate, LTC4, p-aminohippuric acid, ochratoxin-A [139] Unknown Unknown Unknown ABCA9 (48.2%) Unknown Unknown Macrophages [140] Unknown ABCA10 (49.5%) Unknown Unknown Macrophages [141] Unknown ABCA12 (56.3%) Glucosylceramide [142] Lamellar bodies [143] Keratinocyte [143] Harlequin ichthyosis [144] ABCA13 (51.1%) Unknown Unknown Brain [145] Schizophrenia, bipolar disorder, depression [145] Fig. 1. Putative secondary structure of human ABCA1. Five cyste- ine residues (C75, C309, C1463, C1465 and C1477) involved in the two intramolecular disulfide bonds between ECD1 and ECD2 [73] are indicated. The PEST sequence [59], the 1-5-8-14, the putative calmodulin binding site [29], the PDZ binding motif [27,28] and PKA [38] and CK2 [43] phosphorylation sites are indicated. (Not to scale.) K. Nagao et al. Function and regulation of ABCA1 FEBS Journal 278 (2011) 3190–3203 ª 2011 The Authors Journal compilation ª 2011 FEBS 3191 extracellular lipid acceptor in the plasma, is added to the medium [11,12]. Transcriptional regulation of ABCA1 ABCA1-mediated cholesterol efflux is highly regulated at the transcriptional level. In peripheral cells, such as macrophages and fibroblasts, ABCA1 gene expression is enhanced by loading cholesterol [13]. This response is mediated by the nuclear receptors LXRa and LXRb, whose ligands are sterol metabolites such as 22-(R)-hydroxycholesterol, 24-(S)-hydroxycholesterol, 27-hydroxycholesterol and 24-(S),25-epoxycholesterol [14,15]. LXRb is ubiquitously expressed, whereas LXRa is restricted to the liver, adipose tissue, adrenal glands, intestine, lungs, kidneys and cells of myeloid origin. Human LXRa expression is highly regulated and can be autoregulated by itself, whereas human LXRb is stably expressed even in the absence of excess cholesterol. In the basal state, LXR b and retinoid X receptor (RXR) heterodimers are bound to liver X response elements (LXREs) in the promoters of target genes [16] (Fig. 2). When cholesterol accumulates in cells, intracellular con- centrations of oxysterols increase; subsequently, LXRb, activated via the binding of oxysterols, stimulates the transcription of ABCA1 [17–19] and also of LXRa. Interestingly, cholesterol feeding of mice or rats has failed to show a significant increase in hepatic ABCA1 mRNA expression [20]. A promoter region, which responds to sterol regulatory element binding protein 2 (SREBP-2), was identified in the first intron of the ABCA1 gene and was reported to be involved in the reg- ulation of ABCA1 expression in the liver [21]. Recently, MiR-33, an intronic microRNA located within the gene encoding SREBP-2, a transcriptional regulator of cho- lesterol synthesis, was found to modulate the expression of ABCA1 at the post-transcriptional level [22,23]. An elaborate network of regulations has evolved to modu- late cholesterol synthesis and efflux to maintain choles- terol homeostasis. Post-translational regulation of ABCA1 activity ABCA1-mediated cholesterol efflux is also highly regu- lated at the post-translational level. Because cholesterol is an essential component of cells, excessive elimination of cholesterol can result in cell death. Consequently, the ability to rapidly degrade ABCA1 in order to prevent excessive elimination is also important. Indeed, ABCA1 protein turns over rapidly, with a half-life of 1–2 h [24–28]. Several proteins, including a1-syntrophin, A In the absence of excess cholesterol B When cholesterol accumulates PC Chol apoA-I HDL ABCA1 ABCA1 LXRβ/RXR LXRα RXR Oxysterol A LXRβ RXR ABCA1 Cholesterol BCA1 Fig. 2. LXR regulates ABCA1 not only in transcriptional level but also in post-translational level by direct binding. In addition to its well- defined role in transcription, LXRb directly binds the C-terminal region of ABCA1 to mediate its post-translational regulation. (A) In the absence of cholesterol accumulation, LXRb ⁄ RXR heterodimer binds to the C-terminal region of ABCA1. The ABCA1–LXRb ⁄ RXR complex sta- bly localizes to the plasma membrane, but is inactive in HDL formation (30,147). (B) When excess cholesterol accumulates, oxysterols bind to LXRb leading to its dissociation from ABCA1. Because ABCA1 turns over rapidly with a half-life of 1–2 h, and because the transcription, splicing, translation and maturation of ABCA1, at more than 2000 amino acid residues, takes several hours after transcriptional activation, cells cannot cope with an acute accumulation of cholesterol for several hours. This post-translational regulation allows ABCA1 to cause an immediate early response against acute cholesterol accumulation. LXRb has at least two distinct roles in controlling cholesterol homeostasis (modified from [148]). Function and regulation of ABCA1 K. Nagao et al. 3192 FEBS Journal 278 (2011) 3190–3203 ª 2011 The Authors Journal compilation ª 2011 FEBS b1-syntrophin, calmodulin and apoA-I have been reported to interact with ABCA1 and reduce the rate of ABCA1 protein degradation [25–29]. The degradation of ABCA1 is regulated [27,28,30] and is carried out via several pathways: (a) cell-surface ABCA1 is endocytosed and recycled back to the plasma membrane or delivered to the lysosomes through early and late endosomes for degradation [31,32]; (b) calpain protease degrades ABCA1 on the plasma membrane [25,26] and intracellularly, especially when apoA-I does not bind to ABCA1 [33]. ABCA1 is also degraded through the ubiquitin–proteasome path- way [34,35]. COP9 signalosome complex, which plays an important role in the degradation of various proteins such as IjBa, associates with ABCA1 and controls the ubiquitinylation and deubiquitinylation of ABCA1 [36]. Several protein kinases including protein kinase A (PKA), protein kinase C (PKC), Janus kinase 2 (JAK2) and casein kinase (CK2) are involved in the regulation of ABCA1 activity and stability by apoA-I. The inter- action of apoA-I with ABCA1 increases the cellular cAMP content and ABCA1 phosphorylation [37]. This phosphorylation is important for ABCA1 activity, as apoA-I-dependent phospholipid efflux is decreased sig- nificantly by the mutation of the PKA phosphorylation site, Ser-2054, of ABCA1 [38]. ApoA-I also activates PKCa and phosphorylation of ABCA1 [39,40]. This reaction leads to the protection of ABCA1 from its degradation by calpain. On the other hand, phosphory- lation of Thr-1286 and Thr-1305 in the PEST sequence (rich in proline, glutamic acid, serine and threonine) (Fig. 1) within the cytoplasmic domain of ABCA1 pro- motes calpain degradation and is reversed by apoA-I [41]. Unsaturated fatty acids destabilize ABCA1 by phosphorylation through a PKCd pathway [42]. Phos- phorylation of Thr-1242, Thr-1243 and Ser-1255 by CK2 decreases the ABCA1 flippase activity, apoA-I binding and lipid efflux [43]. Calmodulin interacts with ABCA1 at a close or overlapping position to the CK2 phosphorylation site and this interaction regulates calpain-mediated ABCA1 degradation [29]. The inter- action of apoA-I with ABCA1 for only minutes stimu- lates autophosphorylation of JAK2, which in turn activates ABCA1-dependent lipid efflux [44]. Interest- ingly, the apoA-I-mediated activation of JAK2 also activates STAT3, which is independent of the lipid efflux activity of ABCA1. The apoA-I ⁄ ABCA1 path- way in macrophages is proposed to function as an anti- inflammatory receptor through activation of JAK2 ⁄ STAT3 [45]. Cyclosporine A and FK506 were reported to abolish ABCA1-dependent lipid efflux by inhibiting the Ca 2+ -dependent calcineurin ⁄ JAK2 pathway [46]. CDC42, a member of the Rho GTPase family, is reported to interact with ABCA1 and the interaction enhances apoA-I-mediated cholesterol efflux [47]. Palm- itoylation of ABCA1 is also involved in the trafficking and function of ABCA1 [48]. We have reported [30] that the LXRb ⁄ RXR complex binds to ABCA1 when the intracellular concentration of oxysterols is low, and the ABCA1–LXRb ⁄ RXR complex is distributed on the plasma membrane but is inert in terms of cholesterol efflux (Fig. 2). When cho- lesterol accumulates and the intracellular concentration of oxysterols increases, oxysterols bind to LXRb and the LXRb ⁄ RXR complex dissociates from ABCA1. Once free from LXRb ⁄ RXR, ABCA1 is active in the formation of HDL and decreases the local cholesterol concentration immediately. Upon binding to oxysterols, LXRb ⁄ RXR activates the transcription of ABCA1 and other genes. Consequently, LXRb can cause a post- translational response, as well as a transcriptional response, to maintain cholesterol homeostasis. This novel mechanism is an immediate early response to cope with rapid increases in intracellular cholesterol, such as when macrophages consume apoptotic cells. Effects of Tangier mutations on ABCA1 From patients with Tangier disease and familial hypo- alphalipiproteinaemia, more than 70 mutations have been identified in the ABCA1 gene. Most mutations reside in extracellular domains (ECDs) (putative apoA- I binding site) and nucleotide binding domains (NBDs) (driving-force-supplying site) of ABCA1 [3] (Fig. 1). Mutations can be categorized into three groups (Table 2). The first is the ‘maturation defect mutant’ and the majority of mutations belong to this group. Wild-type ABCA1, modified with complex oligosaccha- rides, is mainly localized to the plasma membrane and sometimes in the intracellular compartments [11,31]; however, maturation defect mutants of ABCA1, modi- fied with high mannose type oligosaccharides, have impaired trafficking and are localized inappropriately to the endoplasmic reticulum [10,11,49]. Because apoA-I interacts with ABCA1 on the cell surface, mutants which do not reach the plasma membrane are unable to mediate apoA-I-dependent lipid efflux. The second group is the ‘apoA-I binding defect mutant’. This group is represented by the C1477R mutant of the second ECD (Table 2). Although C1477R mutant is expressed in the plasma membrane like wild-type ABCA1, apoA-I binding is abolished [9,10,49,50]. The third group is the ‘lipid translocation defect mutant’, represented by the W590S mutation in the first ECD of ABCA1 (Table 2). The subcellular distribution of K. Nagao et al. Function and regulation of ABCA1 FEBS Journal 278 (2011) 3190–3203 ª 2011 The Authors Journal compilation ª 2011 FEBS 3193 W590S is indistinguishable from that of wild-type ABCA1. Furthermore, W590S mutation does not affect apoA-I binding [9,10,49,50]; however, W590S mutation reduced phosphatidylserine (PS) flopping activity of ABCA1, detected with the annexin V binding assay [49], and impaired sodium taurocholate-dependent cho- lesterol and phospholipid efflux by ABCA1 [51]. These results suggest that W590S mutation affects the lipid translocation activity of ABCA1 and that the two activities of ABCA1 (apoA-I binding and lipid translo- cation) can be separable (Fig. 3A). Additionally, W590S mutation retarded the dissociation of apoA-I from ABCA1 [51]. Lipid translocation by ABCA1 is supposed to facilitate the dissociation of apoA-I from ABCA1. ApoA-I is reported to undergo a conforma- tional transition in response to lipid [52], and lipidated apoA-I does not interact with ABCA1 [53,54]. The con- formational transition of apoA-I caused by lipid load- ing during binding to ABCA1 may facilitate the dissociation of apoA-I from ABCA1 [55] (Fig. 3A). Subcellular localization and function of ABCA1 ABCA1 localizes mainly to the plasma membrane but sometimes also localizes in the intracellular compart- ments. Two distinct mechanisms have been proposed for ABCA1-mediated HDL formation. One is that ABCA1 mediates the complex formation of apoA-I with phospholipids and cholesterol on the cell surface (cell-surface model), and the other is that apoA-I binds to ABCA1 on the cell surface and ABCA1 ⁄ apoA-I complexes are subsequently internalized. ApoA-I⁄ lipid complexes are formed (probably via ABCA1 activity) in late endosomes and re-secreted by exocytosis (retro- endocytosis model). Takahashi and Smith [56] first showed that, following internalization, apoA-I is recycled back to the cell surface to be re-secreted. The internalized ABCA1 and apoA-I were reported to co-localize within late endosomes, and ABCA1 rapidly shuttled between intracellular compartments and the plasma membrane [31,57]. Trapping ABCA1 on the plasma membrane by cyclosporine A treatment reduces apoA-I-mediated cholesterol efflux [58]. Deletion of the PEST sequence blocks its endocytosis and decreases apoA-I-mediated efflux of cholesterol after loading the late endosome ⁄ lysosome pool of cholesterol by Fig. 3. Membrane meso-domain organization and reorganization by ABCA1. (A) Two proposed mechanisms for HDL formation. (i) Membrane phospholipids and cholesterol are translocated by ABCA1 and (ii) are loaded to apoA-I directly bound to the ECDs of ABCA1 to generate nascent HDL particles [55]. (iii) Membrane phospholipid translocation via ABCA1 induces bending of the mem- brane bilayer to create high curvature sites, to which apoA-I binds and solubilizes membrane phospholipid and cholesterol to create nascent HDL particles [95]. (B) Regulation of cell signalling by ABCA1. (i) ABCA1 translocates membrane phospholipids and cho- lesterol and (iv) changes membrane meso-damain organization, such as lipid rafts, that lead to suppressed receptor-mediated sig- nalling events [99]. Table 2. Effects of mutations on the functions of ABCA1. Class Effects of mutations Position of mutations PM localization ApoA-I binding HDL formation ECD1 TMD1 NBD1 ECD2 TMD2 NBD2 I Defect Defect Defect R587W a,b Q597R a–c DL693 b,c N935S b A1046D b M1091T b S1506L b N1800H b,d R2081W b II Normal Defect Defect C1477R b,c III Normal Normal Defect A255T b W590S a–e T929I b C1660R f a [11]. b [10]. c [49]. d N1800 is predicted to reside in the loop between TM11 and TM12. e [9]. f [146]. Function and regulation of ABCA1 K. Nagao et al. 3194 FEBS Journal 278 (2011) 3190–3203 ª 2011 The Authors Journal compilation ª 2011 FEBS acetylated low-density lipoprotein treatment [59]. These results together support the idea that nascent lipopro- tein particles are formed in intracellular compartments and subsequently secreted from the cell. There are also many reports that ABCA1-mediated cholesterol efflux to apoA-I mainly occurs on the cell surface and that the retroendocytosis pathway does not contribute significantly to HDL formation [33,60,61]. The majority of internalized apoA-I is directly transported to late endosomes and lysosomes for degradation, and blocking endocytosis does not decrease apoA-I-dependent cholesterol efflux. Although apoA-I is specifically taken up by macro- phages, only a small fraction of apoA-I is re-secreted from these cells. Furthermore, the majority of re-secreted apoA-I is degraded in the medium, suggest- ing that the mass of retroendocytosed apoA-I is not sufficient to account for HDL formation; however, these studies were performed using macrophages and other cells without cholesterol loading. As pointed out by Oram [62], the mechanism of HDL formation is probably different whether excess cholesterol has accumulated within cells or not. ABCA1 and apoA-I are endocytosed via a clathrin- and Rab5-mediated pathway and recycled rapidly back to the cell surface, at least in part via a Rab4-mediated route; approximately 30% of the endocytosed ABCA1 is recycled back to the cell surface [32]. When clathrin- mediated endocytosis is inhibited, the level of ABCA1 at the cell surface increases and apoA-I internalization is blocked. Under these conditions, apoA-I-mediated cholesterol efflux from cells that have accumulated lipoprotein-derived cholesterol is decreased, whereas efflux from cells without excess cholesterol is increased [32]. These results suggest that the retroendocytosis pathway of ABCA1 ⁄ apoA-I contributes to HDL for- mation when excess lipoprotein-derived cholesterol has accumulated in cells. This study is also in agreement with previous studies that blocking retroendocytosis of ABCA1 does not affect cholesterol efflux from cells in the absence of excess cholesterol [33,60,61]. ABCA1 probably follows the same constitutive recycling path- way as the LDL receptor [63]. Lipid acceptor for ABCA1 Because cholesterol and phospholipids are very hydro- phobic, lipid acceptors which solubilize them in aque- ous solutions are required for lipid secretion. Under physiological conditions, apoA-I and apoE, containing amphipathic helices, function as acceptors of lipids secreted into serum by ABCA1. Although other amphipathic-helical-peptide-containing proteins (e.g. apoA-II, apoC-I, C-II, C-III, PLTP and serum amy- loid A) also function as lipid acceptors for ABCA1- dependent cholesterol efflux, their physiological contri- butions remain to be clarified [64–67]. Synthetic amphipathic helical peptide (37pA) also promotes cho- lesterol and phospholipid efflux from ABCA1-express- ing cells [68,69]. Furthermore, the 37pA peptide synthesized with d amino acids is as effective as that with l amino acids. From these results, the amphi- pathic helix is considered to be a key structural motif for peptide-mediated lipid efflux from ABCA1 [68]. We reported that sodium taurocholate can also serve as an acceptor for cholesterol and phospholipids trans- located by ABCA1 [51]; therefore, the detergent-like property of the amphipathic helix might be important as a lipid acceptor. It is proposed that apoA-I directly binds to ABCA1 in the process of HDL formation, shown by several groups via crosslinking experiments [54,65,70–72]. Because the 3-A ˚ crosslinker can crosslink apoA-I with ABCA1, the pair of reactive amino acids of ABCA1 and apoA-I are within a distance of £ 3A ˚ [70]. Hozoji et al. found that two intramolecular disulfide bonds are formed between ECD1 and ECD2 of ABCA1, and these two disulfide bonds are necessary for apoA-I binding and HDL formation [73] (Fig. 1). It is reported that apoA-I is not crosslinked with the ATPase-deficient mutant form of ABCA1 [74]. Fur- thermore, fluorescent-labelled apoA-I does not bind to cells expressing ATPase-deficient mutant [51,75]. These results suggest that the large ECD of ABCA1 is the direct binding site for apoA-I and its ATP-dependent conformational change is required for apoA-I binding. But, it is also proposed that apoA-I interacts with a special domain on the plasma membrane apart from ABCA1 and solubilizes membrane lipids. Transport substrates Substrates transported directly by ABCA1 are still controversial [55] (Table 1). Several models have been proposed for the mechanism of ABCA1-mediated HDL formation: (a) a two-step process model in which ABCA1 first mediates PC efflux to apoA-I, and this apoA-I–PC complex accepts cholesterol in an ABCA1- independent manner; (b) a concurrent process model in which PC and cholesterol efflux by ABCA1 to apoA-I are coupled to each other; and (c) a third model in which ABCA1 generates a specific apoA-I binding site on the plasma membrane with subsequent translocation of PC and cholesterol to apoA-I. When it was proposed [74,76], the two-step model looked the most plausible, because photoactive PC could be crosslinked with K. Nagao et al. Function and regulation of ABCA1 FEBS Journal 278 (2011) 3190–3203 ª 2011 The Authors Journal compilation ª 2011 FEBS 3195 ABCA1 whereas direct binding of photoactive choles- terol to ABCA1 could not be detected [74]; however, analysis of the functions of ABCA7 raised questions about this model. Human ABCA7, which has the high- est homology (69.3%) to ABCA1, mediates the apoA-I- dependent efflux of PC and cholesterol, similar to ABCA1 [77]; however, human ABCA7 mediates choles- terol release much less efficiently than ABCA1 [78], and PC but not cholesterol are loaded onto apoA-I by mouse ABCA7 [79]. These results cannot be explained by the two-step process model. Instead, they suggest that ABCA1 has higher affinity for cholesterol trans- port than ABCA7, and are consistent with the concur- rent process model [80]. The third model was originally that ABCA1 mediates the translocation of PS to the outer leaflet to form a special membrane domain, where apoA-I binds and solubilizes membrane lipids [81]. Membrane meso-domain organization and reorganization On the plasma membrane, various meso-scale (10– 100 nm) domains, such as lipid rafts [82], are supposed to be dynamically organized and reorganized and involved in various cellular functions, such as signal transduction. ABCA1 is involved in membrane meso- domain reorganization, as ABCA1 expression results in a significant redistribution of cholesterol and sphin- gomyelin (SM) from Triton X-100-resistant membrane domains [83]. Caveolin also redistributes from punctu- ate caveolae-like structures to the general area of the plasma membrane [83]. Macrophages from ABCA1- deficient mice exhibited increased lipid rafts on the cell surface [84] and ABCA1 made cells more sensitive to methyl-b-cyclodextrin (MbCD) treatment [80] and generated cholesterol-oxidase-accessible membrane domains [85]. Importantly, membrane meso-domain reorganization by ABCA1 is independent of apoA-I [83,85]. It is possi- ble that active lipid translocation via ABCA1, the flop of phospholipids and cholesterol from the inner to outer leaflet, leads to membrane destabilization. Since ABCA1 is not associated with Triton X-100-resistant membrane domains [86,87], the domains are destabi- lized via lipid translocation by ABCA1 located outside the domains. It is reported that ABCA1 is associated with Luburol WX-resistant membranes in cholesterol- loaded monocyte-derived macrophages [87], that ABCA1 and flotillin-1 are co-localized in these deter- gent-resistant membranes and can be co-precipitated [88], and that expression of caveolin-1 enhances apoA- I-dependent cholesterol efflux in hepatic cells [89]. ABCA1 may localize just outside Triton X-100-resistant membrane domains. But ABCA1 is not recovered from either Triton X-100- or Luburol WX-resistant mem- branes in fibroblasts [87]. It is not clear how lipid trans- location by ABCA1 in non-raft regions reorganizes other domains of the plasma membrane. We analysed the effects of the cellular SM level on the function of ABCA1 using a CHO-K1 mutant cell line, LY-A [90], which has a missense mutation in the ceramide transfer protein CERT, and reported that the decrease in SM content in the plasma membrane stim- ulates apoA-I-dependent cholesterol efflux by ABCA1 [91]. The amount of cholesterol available to cold MbCD extraction is increased when SM content is reduced. However, apoA-I-dependent cholesterol efflux is not observed without ABCA1 expression even when SM content is reduced, suggesting that the cholesterol available to cold MbCD cannot be loaded onto apoA- I spontaneously. When ABCA1 is expressed, the cho- lesterol available to cold MbCD is increased by 40%. This effect of ABCA1 is independent of apoA-I. These results suggest that ABCA1 translocates membrane lipids in detergent-soluble domains and makes (acti- vates [92] or projects [55]) cholesterol available to cold MbCD. The effect of the reduction of plasma mem- brane SM content on the function of ABCA1 is quite different from that on the function of ABCG1, since ABCG1-mediated cholesterol efflux decreases when cellular SM content is reduced [93]. This is consistent with previous reports that lipids loaded onto lipid-poor apoA-I by ABCA1 are provided by Triton X-100-sen- sitive membrane domains, whereas lipids loaded onto HDL, the lipid acceptor for ABCG1, are derived from Triton X-100-resistant membrane domains [86,87], and that treating rat fibroblasts with SMase increased apoA-I- or apo-E-dependent cholesterol efflux [94]. Several studies suggest that ABCA1 generates spe- cial membrane meso-domains. Membrane phospho- lipid translocation via ABCA1 induces bending of the membrane bilayer to create high curvature sites, such as is created in 20-nm-diameter small unilamellar vesi- cles, to which apoA-I binds and solubilizes membrane phospholipid and cholesterol to create nascent HDL particles [95] (Fig. 3A). In agreement with this concept, plasma membrane protrusions [54] and apoA-I binding to protruding plasma membrane domains [96] have been observed in cells expressing ABCA1. Such apoA-I binding could be enhanced by PS molecules translocated to the exofacial leaflet by ABCA1 [81], because the presence of PS enhances vesicle curvature [97]. How- ever, there are still clear differences in the dependence on apoA-I concentration between ABCA1-mediated lipid efflux and in vitro solubilization of phospholipid vesicles [95]. It has been calculated that only a portion Function and regulation of ABCA1 K. Nagao et al. 3196 FEBS Journal 278 (2011) 3190–3203 ª 2011 The Authors Journal compilation ª 2011 FEBS of the apoA-I associated with the cell surface binds directly to ABCA1 [72,98]. One plausible explanation may be that direct interaction with ABCA1 causes conformational changes in apoA-I to make it open and receptive to lipids. Activated apoA-I may interact with the special meso-domains created by ABCA1. Recently it was reported that LXR signalling at a metabolic checkpoint modulates T cell proliferation and immunity [99]. T cell activation is accompanied by the downregulation of LXR target genes, ABCA1 and ABCG1 [100]. Loss of LXR expression confers a pro- liferative advantage to lymphocytes, resulting in enhanced homeostatic and antigen-driven responses. Conversely, ligand activation of LXR inhibits mitogen- driven T cell expansion. Cellular cholesterol is required for increased membrane synthesis during cell prolifera- tion. Additional mechanisms may also be involved, such as changes in membrane meso-domain organiza- tion, e.g. lipid rafts, that lead to enhanced receptor- mediated signalling events. Functional deficiencies of ABCA1 and ABCG1 cause enhanced inflammatory responses of macrophages, especially after treatment with lipopolysaccharide or other toll-like receptor ligands [84,101–103]. ABCA1 and ABCG1 may pro- mote membrane lipid redistribution [83,104], which modulates raft-dependent cell signalling (Fig. 3B). Acknowledgements This study was supported by a Grant-in-aid for Scien- tific Research (S) from the Ministry of Education, Cul- ture, Sports, Science and Technology of Japan, the Bio-oriented Technology Research Advancement Insti- tution, and the World Premier International Research Center Initiative, MEXT, Japan. References 1 van Dam MJ, de Groot E, Clee SM, Hovingh GK, Roelants R, Brooks-Wilson A, Zwinderman AH, Smit AJ, Smelt AH, Groen AK et al. (2002) Association between increased arterial-wall thickness and impair- ment in ABCA1-driven cholesterol efflux: an observa- tional study. Lancet 359, 37–42. 2 Frikke-Schmidt R (2010) Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population. Atherosclerosis 208, 305–316. 3 Singaraja RR, Brunham LR, Visscher H, Kastelein JJ & Hayden MR (2003) Efflux and atherosclerosis: the clinical and biochemical impact of variations in the ABCA1 gene. Arterioscler Thromb Vasc Biol 23, 1322–1332. 4 Oram JF & Vaughan AM (2006) ATP-binding cassette cholesterol transporters and cardiovascular disease. Circ Res 99, 1031–1043. 5 Bodzioch M, Orso E, Klucken J, Langmann T, Bott- cher A, Diederich W, Drobnik W, Barlage S, Buchler C, Porsch-Ozcurumez M et al. (1999) The gene encod- ing ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22, 347–351. 6 Brooks-Wilson A, Marcil M, Clee S, Zhang L, Roomp K, van Dam M, Yu L, Brewer C, Collins J, Molhuizen H et al. (1999) Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22, 336–345. 7 Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette J, Deleuze J, Brewer H, Duverger N, Denefle P et al. (1999) Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22, 352–355. 8 Brunham LR, Singaraja RR & Hayden MR (2006) Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis. Annu Rev Nutr 26, 105–129. 9 Fitzgerald ML, Morris AL, Rhee JS, Andersson LP, Mendez AJ & Freeman MW (2002) Naturally occur- ring mutations in ABCA1’s largest extracellular loops can disrupt its direct interaction with apolipoprotein A-I. J Biol Chem 277, 33178–33187. 10 Singaraja RR, Visscher H, James ER, Chroni A, Coutinho JM, Brunham LR, Kang MH, Zannis VI, Chimini G & Hayden MR (2006) Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro. Circ Res 99, 389–397. 11 Tanaka AR, Abe-Dohmae S, Ohnishi T, Aoki R, Morinaga G, Okuhira KI, Ikeda Y, Kano F, Matsuo M, Kioka N et al. (2003) Effects of mutations of ABCA1 in the first extracellular domain on subcellular trafficking and ATP binding ⁄ hydrolysis. J Biol Chem 278, 8815–8819. 12 Yokoyama S (2000) Release of cellular cholesterol: molecular mechanism for cholesterol homeostasis in cells and in the body. Biochim Biophys Acta 1529, 231–244. 13 Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, Seilhamer JJ, Vaughan AM & Oram JF (1999) The Tangier disease gene product ABC1 con- trols the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest 104, R25–31. 14 Janowski BA, Willy PJ, Devi TR, Falck JR & Mangelsdorf DJ (1996) An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383, 728–731. 15 Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blan- chard DE, Spencer TA et al. (1997) Activation of the K. Nagao et al. Function and regulation of ABCA1 FEBS Journal 278 (2011) 3190–3203 ª 2011 The Authors Journal compilation ª 2011 FEBS 3197 nuclear receptor LXR by oxysterols defines a new hor- mone response pathway. J Biol Chem 272, 3137–3140. 16 Bischoff ED, Daige CL, Petrowski M, Dedman H, Pattison J, Juliano J, Li AC & Schulman IG (2010) Non-redundant roles for LXRalpha and LXRbeta in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice. J Lipid Res 51, 900–906. 17 Venkateswaran A, Laffitte BA, Joseph SB, Mak PA, Wilpitz DC, Edwards PA & Tontonoz P (2000) Con- trol of cellular cholesterol efflux by the nuclear oxys- terol receptor LXR alpha. Proc Natl Acad Sci USA 97, 12097–12102. 18 Repa JJ, Turley SD, Lobaccaro J-MA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM & Mangelsdorf DJ (2000) Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289, 1524–1529. 19 Costet P, Luo Y, Wang N & Tall AR (2000) Sterol- dependent transactivation of the ABC1 promoter by the liver X receptor ⁄ retinoid X receptor. J Biol Chem 275, 28240–28245. 20 Engelking LJ, Kuriyama H, Hammer RE, Horton JD, Brown MS, Goldstein JL & Liang G (2004) Overex- pression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimu- lated lipogenesis. J Clin Invest 113, 1168–1175. 21 Tamehiro N, Shigemoto-Mogami Y, Kakeya T, Okuh- ira K, Suzuki K, Sato R, Nagao T & Nishimaki-Mo- gami T (2007) Sterol regulatory element-binding protein-2- and liver X receptor-driven dual promoter regulation of hepatic ABC transporter A1 gene expres- sion: mechanism underlying the unique response to cel- lular cholesterol status. J Biol Chem 282, 21090–21099. 22 Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Co- hen DE, Gerszten RE & Naar AM (2010) MicroRNA- 33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 328, 1566–1569. 23 Rayner KJ, Suarez Y, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ & Fernandez-Hernando C (2010) MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328, 1570–1573. 24 Wang Y & Oram JF (2002) Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increas- ing degradation of ATP-binding cassette transporter A1. J Biol Chem 277, 5692–5697. 25 Arakawa R & Yokoyama S (2002) Helical apolipopro- teins stabilize ATP-binding cassette transporter A1 by protecting it from thiol protease-mediated degradation. J Biol Chem 277, 22426–22429. 26 Wang N, Chen W, Linsel-Nitschke P, Martinez LO, Agerholm-Larsen B, Silver DL & Tall AR (2003) A PEST sequence in ABCA1 regulates degradation by calpain protease and stabilization of ABCA1 by apoA-I. J Clin Invest 111, 99–107. 27 Munehira Y, Ohnishi T, Kawamoto S, Furuya A, Shitara K, Imamura M, Yokota T, Takeda S, Amachi T, Matsuo M et al. (2004) Alpha1-syntrophin modulates turnover of ABCA1. J Biol Chem 279, 15091–15095. 28 Okuhira K, Fitzgerald ML, Sarracino DA, Manning JJ, Bell SA, Goss JL & Freeman MW (2005) Purifica- tion of ATP-binding cassette transporter A1 and asso- ciated binding proteins reveals the importance of beta1-syntrophin in cholesterol efflux. J Biol Chem 280, 39653–39664. 29 Iwamoto N, Lu R, Tanaka N, Abe-Dohmae S & Yokoyama S (2010) Calmodulin interacts with ATP binding cassette transporter A1 to protect from calpain-mediated degradation and upregulates high- density lipoprotein generation. Arterioscler Thromb Vasc Biol 30, 1446–1452. 30 Hozoji M, Munehira Y, Ikeda Y, Makishima M, Matsuo M, Kioka N & Ueda K (2008) Direct inter- action of nuclear liver X receptor-beta with ABCA1 modulates cholesterol efflux. J Biol Chem 283, 30057– 30063. 31 Neufeld EB, Remaley AT, Demosky SJ, Stonik JA, Cooney AM, Comly M, Dwyer NK, Zhang M, Blanchette-Mackie J, Santamarina-Fojo S et al. (2001) Cellular localization and trafficking of the human ABCA1 transporter. J Biol Chem 276, 27584–27590. 32 Azuma Y, Takada M, Shin H-W, Kioka N, Nakay- ama K & Ueda K (2009) Retroendocytosis pathway of ABCA1 ⁄ apoA-I contributes to HDL formation. Genes Cells 14, 191–204. 33 Lu R, Arakawa R, Ito-Osumi C, Iwamoto N & Yokoyama S (2008) ApoA-I facilitates ABCA1 recycle ⁄ accumulation to cell surface by inhibiting its intracellular degradation and increases HDL genera- tion. Arterioscler Thromb Vasc Biol 28, 1820–1824. 34 Feng B & Tabas I (2002) ABCA1-mediated cholesterol efflux is defective in free cholesterol-loaded macro- phages. Mechanism involves enhanced ABCA1 degra- dation in a process requiring full NPC1 activity. J Biol Chem 277, 43271–43280. 35 Tanaka AR, Kano F, Yamamoto A, Ueda K & Murata M (2008) Formation of cholesterol-enriched structures by aberrant intracellular accumulation of ATP-binding cassette transporter A1. Genes Cells 13, 889–904. 36 Azuma Y, Takada M, Maeda M, Kioka N & Ueda K (2009) The COP9 signalosome controls ubiquitinyla- tion of ABCA1. Biochem Biophys Res Commun 382, 145–148. 37 Haidar B, Denis M, Marcil M, Krimbou L & Genest J Jr (2004) Apolipoprotein A-I activates cellular cAMP signaling through the ABCA1 transporter. J Biol Chem 279, 9963–9969. 38 See RH, Caday-Malcolm RA, Singaraja RR, Zhou S, Silverston A, Huber MT, Moran J, James ER, Janoo Function and regulation of ABCA1 K. Nagao et al. 3198 FEBS Journal 278 (2011) 3190–3203 ª 2011 The Authors Journal compilation ª 2011 FEBS R, Savill JM et al. (2002) Protein kinase A site-specific phosphorylation regulates ATP-binding cassette A1 (ABCA1)-mediated phospholipid efflux. J Biol Chem 277, 41835–41842. 39 Yamauchi Y, Hayashi M, Abe-Dohmae S & Yokoy- ama S (2003) Apolipoprotein A-I activates protein kinase C alpha signaling to phosphorylate and stabilize ATP binding cassette transporter A1 for the high den- sity lipoprotein assembly. J Biol Chem 278, 47890– 47897. 40 Yamauchi Y, Chang CC, Hayashi M, Abe-Dohmae S, Reid PC, Chang TY & Yokoyama S (2004) Intracellu- lar cholesterol mobilization involved in the ABCA1 ⁄ apolipoprotein-mediated assembly of high density lipoprotein in fibroblasts. J Lipid Res 45, 1943–1951. 41 Martinez LO, Agerholm-Larsen B, Wang N, Chen W & Tall AR (2003) Phosphorylation of a PEST sequence in ABCA1 promotes calpain degradation and is reversed by ApoA-I. J Biol Chem 278, 37368–37374. 42 Wang Y & Oram JF (2007) Unsaturated fatty acids phosphorylate and destabilize ABCA1 through a pro- tein kinase C delta pathway. J Lipid Res 48, 1062– 1068. 43 Roosbeek S, Peelman F, Verhee A, Labeur C, Caster H, Lensink MF, Cirulli C, Grooten J, Cochet C, Van- dekerckhove J et al. (2004) Phosphorylation by protein kinase CK2 modulates the activity of the ATP binding cassette A1 transporter. J Biol Chem 279, 37779– 37788. 44 Tang C, Vaughan AM & Oram JF (2004) Janus kinase 2 modulates the apolipoprotein interactions with ABCA1 required for removing cellular cholesterol. J Biol Chem 279, 7622–7628. 45 Tang C, Liu Y, Kessler PS, Vaughan AM & Oram JF (2009) The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor. J Biol Chem 284, 32336–32343. 46 Karwatsky J, Ma L, Dong F & Zha X (2010) Choles- terol efflux to apoA-I in ABCA1-expressing cells is regulated by Ca 2+ -dependent calcineurin signaling. J Lipid Res 51, 1144–1156. 47 Nofer JR, Remaley AT, Feuerborn R, Wolinnska I, Engel T, von Eckardstein A & Assmann G (2006) Apolipoprotein A-I activates Cdc42 signaling through the ABCA1 transporter. J Lipid Res 47, 794–803. 48 Singaraja RR, Kang MH, Vaid K, Sanders SS, Vilas GL, Arstikaitis P, Coutinho J, Drisdel RC, El-Husse- ini Ael D, Green WN et al. (2009) Palmitoylation of ATP-binding cassette transporter A1 is essential for its trafficking and function. Circ Res 105, 138–147. 49 Rigot V, Hamon Y, Chambenoit O, Alibert M, Duver- ger N & Chimini G (2002) Distinct sites on ABCA1 control distinct steps required for cellular release of phospholipids. J Lipid Res 43, 2077–2086. 50 Vaughan AM, Tang C & Oram JF (2009) ABCA1 mutants reveal an interdependency between lipid export function, apoA-I binding activity, and Janus kinase 2 activation. J Lipid Res 50, 285–292. 51 Nagao K, Zhao Y, Takahashi K, Kimura Y & Ueda K (2009) Sodium taurocholate-dependent lipid efflux by ABCA1: effects of W590S mutation on lipid trans- location and apolipoprotein A-I dissociation. J Lipid Res 50, 1165–1172. 52 Davidson WS & Thompson TB (2007) The structure of apolipoprotein A-I in high density lipoproteins. J Biol Chem 282, 22249–22253. 53 Mulya A, Lee JY, Gebre AK, Thomas MJ, Colvin PL & Parks JS (2007) Minimal lipidation of pre-beta HDL by ABCA1 results in reduced ability to interact with ABCA1. Arterioscler Thromb Vasc Biol 27, 1828–1836. 54 Wang N, Silver D, Costet P & Tall A (2000) Specific binding of ApoA-I, enhanced cholesterol efflux, and altered plasma membrane morphology in cells express- ing ABC1. J Biol Chem 275 , 33053–33058. 55 Nagao K, Kimura Y, Mastuo M & Ueda K (2010) Lipid outward translocation by ABC proteins. FEBS Lett 584, 2717–2723. 56 Takahashi Y & Smith JD (1999) Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway. Proc Natl Acad Sci USA 96, 11358–11363. 57 Neufeld EB, Stonik JA, Demosky SJ Jr, Knapper CL, Combs CA, Cooney A, Comly M, Dwyer N, Blanchette-Mackie J, Remaley AT et al. (2004) The ABCA1 transporter modulates late endocytic trafficking: insights from the correction of the genetic defect in Tangier disease. J Biol Chem 279, 15571– 15578. 58 Le Goff W, Peng DQ, Settle M, Brubaker G, Morton RE & Smith JD (2004) Cyclosporin A traps ABCA1 at the plasma membrane and inhibits ABCA1-medi- ated lipid efflux to apolipoprotein A-I. Arterioscler Thromb Vasc Biol 24, 2155–2161. 59 Chen W, Wang N & Tall AR (2005) A PEST deletion mutant of ABCA1 shows impaired internalization and defective cholesterol efflux from late endosomes. J Biol Chem 280, 29277–29281. 60 Denis M, Landry YD & Zha X (2008) ATP-binding cassette A1-mediated lipidation of apolipoprotein A-I occurs at the plasma membrane and not in the endocy- tic compartments. J Biol Chem 283, 16178–16186. 61 Faulkner LE, Panagotopulos SE, Johnson JD, Woollett LA, Hui DY, Witting SR, Maiorano JN & Davidson WS (2008) An analysis of the role of a retro- endocytosis pathway in ABCA1-mediated cholesterol efflux from macrophages. J Lipid Res 49, 1322–1332. 62 Oram JF (2008) The ins and outs of ABCA. J Lipid Res 49, 1150–1151. K. Nagao et al. Function and regulation of ABCA1 FEBS Journal 278 (2011) 3190–3203 ª 2011 The Authors Journal compilation ª 2011 FEBS 3199 [...]... (2007) 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, 242 8–2 442 99 Yvan-Charvet L, Wang N & Tall AR (2010) Role of HDL, ABCA1, and ABCG1 transporters in cholesterol Function and regulation of ABCA1 100 101 102 103 104 105 106 107 108 109 efflux and immune responses... promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine Nat Cell Biol 2, 39 9–4 06 Simons K & Toomre D (2000) Lipid rafts and signal transduction Nat Rev Mol Cell Biol 1, 3 1–3 9 Landry YD, Denis M, Nandi S, Bell S, Vaughan AM & Zha X (2006) ABCA1 expression disrupts raft membrane microdomains through its ATPase-related functions J Biol Chem 281, 3609 1–3 6101 Koseki M,... 15, 23 6–2 46 Shroyer NF, Lewis RA, Yatsenko AN, Wensel TG & Lupski JR (2001) Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and agerelated macular degeneration Hum Mol Genet 10, 267 1–2 678 Weng J, Mata NL, Azarian SM, Tzekov RT, Birch DG & Travis GH (1999) Insights into the function of Rim protein in photoreceptors and etiology of Stargardt’s... efflux to apolipoprotein A-I and formation of high density lipoprotein particles J Biol Chem 282, 2512 3–2 5130 96 Lin G & Oram JF (2000) Apolipoprotein binding to protruding membrane domains during removal of excess cellular cholesterol Atherosclerosis 149, 35 9– 370 97 Hauser H & Phillips MC (1973) Structures of aqueous dispersions of phosphatidylserine J Biol Chem 248, 858 5–8 591 98 Hassan HH, Denis M,... ABCA1- dependent and an ABCA1- independent pathway J Lipid Res 44, 82 8–8 36 69 Arakawa R, Hayashi M, Remaley AT, Brewer BH, Yamauchi Y & Yokoyama S (2004) Phosphorylation and stabilization of ATP binding cassette transporter A1 by synthetic amphiphilic helical peptides J Biol Chem 279, 621 7–6 220 70 Chroni A, Liu T, Fitzgerald ML, Freeman MW & Zannis VI (2004) Cross-linking and lipid efflux properties of. .. Tissue-specific roles of ABCA1 influence susceptibility to atherosclerosis Arterioscler Thromb Vasc Biol 29, 54 8–5 54 Karasinska JM, Rinninger F, Lutjohann D, Ruddle P, Franciosi S, Kruit JK, Singaraja RR, Hirsch-Reinshagen V, Fan J, Brunham LR et al (2009) Specific loss of brain ABCA1 increases brain cholesterol uptake and influences neuronal structure and function J Neurosci 29, 357 9–3 589 Sakai H, Tanaka... in FEBS Journal 278 (2011) 319 0–3 203 ª 2011 The Authors Journal compilation ª 2011 FEBS 3201 Function and regulation of ABCA1 110 111 112 113 114 115 116 117 118 119 120 3202 K Nagao et al abnormal sphingolipid metabolism in mouse brain J Biol Chem 282, 1969 2–1 9699 Vulevic B, Chen Z, Boyd JT, Davis W Jr, Walsh ES, Belinsky MG & Tew KD (2001) Cloning and characterization of human adenosine 5¢-triphosphate-binding... 26 8–2 78 88 Bared SM, Buechler C, Boettcher A, Dayoub R, Sigruener A, Grandl M, Rudolph C, Dada A & Schmitz G (2004) Association of ABCA1 with syntaxin 13 and flotillin-1 and enhanced phagocytosis in tangier cells Mol Biol Cell 15, 539 9–5 407 89 Fu Y, Hoang A, Escher G, Parton RG, Krozowski Z & Sviridov D (2004) Expression of caveolin-1 enhances cholesterol efflux in hepatic cells J Biol Chem 279, 1414 0–1 4146... Posttranscriptional regulation of human ABCA7 and its function for the apoA-I-dependent lipid release Biochem Biophys Res Commun 311, 31 3–3 18 Tsuruoka S, Ishibashi K, Yamamoto H, Wakaumi M, Suzuki M, Schwartz GJ, Imai M & Fujimura A (2002) Functional analysis of ABCA8, a new drug transporter Biochem Biophys Res Commun 298, 4 1–4 5 Piehler A, Kaminski WE, Wenzel JJ, Langmann T & Schmitz G (2002) Molecular structure of. .. transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer J Clin Invest 115, 177 7–1 784 Knight HM, Pickard BS, Maclean A, Malloy MP, Soares DC, McRae AF, Condie A, White A, Hawkins W, McGhee K et al (2009) A cytogenetic abnormality and rare coding variants identify ABCA13 as a candidate gene in schizophrenia, bipolar disorder, and depression Am J Hum Genet 85, 83 3–8 46 Maekawa . MINIREVIEW Function and regulation of ABCA1 – membrane meso-domain organization and reorganization Kohjiro Nagao, Maiko Tomioka and Kazumitsu Ueda Institute. the first ECD of ABCA1 (Table 2). The subcellular distribution of K. Nagao et al. Function and regulation of ABCA1 FEBS Journal 278 (2011) 319 0–3 203 ª 2011