Báo cáo khoa học: Function and regulation of ABCA1 – membrane meso-domain organization and reorganization pptx

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:
(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.
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