Physiol Rev 85: 1343–1372, 2005;
doi:10.1152/physrev.00005.2005.
ATP-Binding Cassette Transporter A1: A Cell Cholesterol
Exporter That Protects Against Cardiovascular Disease
JOHN F. ORAM AND JAY W. HEINECKE
Department of Medicine, University of Washington, Seattle, Washington
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I. Introduction
II. Cell Biology
A. Structure
B. Function
C. Substrates
D. Lipid acceptors
E. Apolipoprotein binding
F. Lipid transport model
III. Regulation
A. Expression
B. Activity
IV. In Vivo Functions
A. HDL production
B. Reverse cholesterol transport
C. Tissue-specific functions
V. ABCA1 and Cardiovascular Disease
A. ABCA1 activity
B. ABCA1-interacting apolipoproteins
VI. ABCA1 as a Therapeutic Target
A. Transcriptional regulation
B. Posttranscriptional regulation
C. Apolipoprotein supply
VII. Conclusions
Oram, John F., and Jay W. Heinecke. ATP-Binding Cassette Transporter A1: A Cell Cholesterol Exporter That
Protects Against Cardiovascular Disease. Physiol Rev 85: 1343–1372, 2005; doi:10.1152/physrev.00005.2005.—Blood
high-density lipoprotein (HDL) levels are inversely related to risk for cardiovascular disease, implying that factors
associated with HDL metabolism are atheroprotective. One of these factors is ATP-binding cassette transporter A1
(ABCA1), a cell membrane protein that mediates the transport of cholesterol, phospholipids, and other metabolites
from cells to lipid-depleted HDL apolipoproteins. ABCA1 transcription is highly induced by sterols, a major substrate
for cellular export, and its expression and activity are regulated posttranscriptionally by diverse processes. Liver
ABCA1 initiates formation of HDL particles, and macrophage ABCA1 protects arteries from developing atherosclerotic lesions. ABCA1 mutations can cause a severe HDL deficiency syndrome characterized by cholesterol deposition in tissue macrophages and prevalent atherosclerosis. Genetic manipulations of ABCA1 expression in mice also
affect plasma HDL levels and atherogenesis. Metabolites elevated in individuals with the metabolic syndrome and
diabetes destabilize ABCA1 protein and decrease cholesterol export from macrophages. Moreover, oxidative
modifications of HDL found in patients with cardiovascular disease reduce the ability of apolipoproteins to remove
cellular cholesterol by the ABCA1 pathway. These observations raise 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 an important new therapeutic target for treating cardiovascular disease.
I. INTRODUCTION
Cholesterol plays several structural and metabolic
roles that are vital to human biology. Although cholesterol
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distributes along the entire plasma membrane of cells,
where it modulates fluidity, it concentrates in specialized
sphingolipid-rich domains called rafts and caveolae (8).
These contain a variety of signaling molecules that de-
0031-9333/05 $18.00 Copyright © 2005 the American Physiological Society
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JOHN F. ORAM AND JAY W. HEINECKE
Physiol Rev • VOL
poproteins) that are associated with no or very little lipid
(204, 287). ABCA1 is highly expressed in the liver and tissue
macrophages (149, 296). ABCA7, a close homolog of ABCA1,
selectively transports phospholipids to lipid-depleted apolipoproteins (1, 116, 133, 140, 164, 285). It is highly expressed
in myelolymphatic tissues, lung, adrenal, and brain. ABCG1
and ABCG4 mediate cholesterol transport from cells to HDL
particles and are highly expressed in tissue macrophages
and brain cells, respectively (120, 188, 202, 244, 284).
ABCA1 has been more extensively characterized
than the other three ABC lipid transporters. Numerous
studies of cultured cells, human HDL deficiencies, and
animal models have shown that ABCA1 is a major determinant of plasma HDL levels and a potent atheroprotective factor (4, 131, 204, 255, 287). This transporter has
therefore become an important new therapeutic target for
drug development designed for clearing cholesterol from
arterial macrophages and preventing CVD. This review
focuses on the biology and pathophysiology of ABCA1.
II. CELL BIOLOGY
A. Structure
ABC transporters are the largest membrane transporter family, with members in all phyla (54). ABCs are
grouped into seven subclasses labeled ABCA through
ABCG. Of the 49 ABCs in humans, 13 are in the ABCA
subclass (54). Mutations in ABC genes cause a variety of
diseases, including cystic fibrosis, Startgardt’s macular
degeneration, and disturbances in lipid and lipoprotein
metabolism. All ABC transporters utilize ATP to generate
the energy needed to transport metabolites across membranes. Structurally, ABCs fall into two groups: 1) whole,
transporters having two similar structural units joined
covalently; and 2) half, transporters of single structural
units that form active heterodimers or homodimers (54).
ABCA1 and ABCA7 are whole transporters, whereas
ABCG1 and ABCG4 are homodimeric half transporters.
ABCA1 is a 2,261-amino-acid integral membrane protein that comprises two halves of similar structure (71).
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 (Fig. 1) (54). ABCA1 is predicted to have an NH2
terminus oriented into the cytosol and two large extracellular loops that are highly glycosylated and linked by one
or more cysteine bonds (Fig. 1) (31, 54).
B. Function
ABCA1 mediates the transport of cholesterol, phospholipids, and other lipophilic molecules across cellular
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pend on a well-maintained cholesterol content for normal
activity. In addition, cholesterol is a substrate for steroid
production and covalently links to a protein involved in
limb development (158). Too much cholesterol in cells,
however, can have pathological consequences. This is
particularly true for cells of the artery wall, where accumulation of cholesterol initiates atherosclerotic cardiovascular disease (CVD) (95). The body therefore relies on
a complex homeostatic network to modulate the availability of cholesterol for tissues. This network operates on both
the cellular level and within the plasma compartment.
Approximately two-thirds of the cholesterol in human plasma is carried in a class of lipoprotein particles
called low-density lipoprotein (LDL). LDL provides a
source of cholesterol for steroidogenesis and cellular
membranes. This occurs through the interaction of LDL
with a cell-surface receptor that mediates internalization
and degradation of the lipoprotein particles (27). The
hepatic LDL receptor is responsible for clearing most of
the LDL cholesterol from the plasma.
Cells other than those in steroidogenic tissues and
the liver cannot metabolize cholesterol. Instead, they
modulate their membrane cholesterol content by a feedback system that controls the rate of cholesterol biosynthesis and uptake by the LDL receptor (26). With most cell
types this system is sufficient to provide cells with enough
cholesterol for membrane integrity and function without
overloading them. Some cells, particularly macrophages,
can ingest cholesterol by endocytotic and phagocytotic
pathways that are not feedback regulated by cholesterol
(213). These cells must either store this excess cholesterol as esters or secrete it.
High-density lipoprotein (HDL), which carries about
one-third of the cholesterol in human plasma, is involved
in the removal of excess cholesterol from cells. HDL is a
multifunctional and heterogeneous class of particles that
transports a variety of lipids and lipophilic molecules
between tissues and other lipoproteins. One of the major
functions of HDL is to transport cholesterol from peripheral tissues to the liver for elimination in the bile (69, 90,
210). This process, called reverse cholesterol transport, is
widely believed to account for much of the inverse relationship between plasma HDL levels and CVD revealed by
population studies.
HDL components can remove cellular cholesterol by
multiple mechanisms (210, 237). 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
(143). Four cell membrane transporters have been identified
that mediate cholesterol efflux from cells to HDL components by metabolically active pathways. All four belong to a
superfamily of ATP-binding cassette transporters (ABCs).
ABCA1 mediates the transport of cellular cholesterol, phospholipids, and other metabolites to HDL proteins (apoli-
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ABCA1 FUNCTION AND PATHOBIOLOGY
FIG. 1. Topological model of ABCA1. This
model is based on domain studies of ABCA1 and
the closely related homolog ABCR (31, 71). Y
indicates approximate glycosylation sites, and S-S
indicates one predicted disulfide bond. NBD-1
and NBD-2 are the nucleotide binding domains
that contain the highly conserved Walker A and
Walker B domains and the Walker C signature
motif.
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(163). It is likely that these structures are formed by the
lipid transport activity of ABCA1, as has been shown for
another ABC phospholipid transporter (52).
Two models have been proposed to account for the
ability of ABCA1 to target specific lipid domains (Fig. 2).
The exocytosis model implies that excess intracellular
cholesterol is packaged into transport vesicles or rafts,
perhaps in the Golgi apparatus, which translocate to domains in the plasma membrane containing ABCA1 (205).
In support of this model are results showing that induction of ABCA1 in the absence of apolipoproteins increases
the appearance of cholesterol on the cell surface (276).
The retroendocytosis model suggests that ABCA1- and
apolipoprotein-containing vesicles endocytose to intracellular lipid deposits, where ABCA1 pumps lipids into the
vesicle lumen for release by exocytosis (242, 261). Consistent with this mechanism are studies showing that
ABCA1 recycles rapidly between the plasma membrane
and late endosomal/lysosomal compartments, that these
compartments accumulate cholesterol in cells with dysfunctional ABCA1, and that ABCA1-containing intracellular vesicles also contain apolipoproteins (193, 194). It is
still unclear, however, which model represents the dominant pathway for ABCA1-dependent lipid efflux.
C. Substrates
ABCA1 appears to mediate the transport of diverse
types of molecules. In addition to cholesterol and phospholipids, ABCA1 has been reported to promote secretion
of ␣-tocopherol (208), apoE (279), and interleukin-1␤
(101, 313). ABCA1-mediated secretion of ␣-tocopherol
mimics that of cholesterol (208), suggesting similar transport mechanisms for these substrates.
ABCA1 can promote phospholipid efflux from cells
even when membranes are depleted of cholesterol (276,
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membranes, where they are removed from cells by lipidpoor HDL apolipoproteins (204). Its homology with other
better-characterized ABC transporters suggests 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 (203, 204). ABCA1 localizes to the plasma membrane and intracellular compartments (193, 194), where it could potentially facilitate
transport of lipids to either cell surface-bound or internalized apolipoproteins.
ABCA1 appears to target specific membrane domains
for lipid secretion. These are likely to be regions that are
sensitive to accumulation of cholesterol and other lipophilic compounds. This same source of cholesterol
feeds into intracellular compartments that are the preferred substrate for the esterifying enzyme acyl CoA:
cholesterol acyltransferase (ACAT) (176, 304). Thus
ABCA1 removes cholesterol that would otherwise accumulate as cytosolic cholesteryl ester lipid droplets. One
possibility for the link between ABCA1 and ACAT is that
both proteins function to protect cells from incorporating
too much free cholesterol into the endoplasmic reticulum
where it may disrupt the peptide biosynthetic machinery.
When cholesterol esterification is blocked in sterol-laden
macrophages, the potentially cytotoxic free cholesterol
that accumulates is a preferred substrate for the ABCA1
pathway (136).
These observations imply that ABCA1 associates
with cholesterol-rich membrane lipid domains. The properties of these domains are unknown, but they appear to
be separate from sphingolipid-rich rafts and caveolae
(177). A fraction of ABCA1, however, may associate with
membrane rafts that are selectively solubilized by the
detergent Lubrol and are relatively enriched with cholesterol and phosphatidylcholine (60). Immunogold electron
microscopy showed that apolipoproteins interact with
diffuse structures protruding from the plasma membrane
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JOHN F. ORAM AND JAY W. HEINECKE
D. Lipid Acceptors
HDL apolipoproteins selectively interact with plasma
membrane lipid domains that are formed by the action of
ABCA1 (86, 87, 166). This interaction is specific for apolipoproteins that contain no or very little lipids. This was
evident from studies showing that purified HDL apolipoproteins promote cholesterol and phospholipid efflux
from cells exclusively by this pathway (75, 226). In contrast, lipidated apolipoproteins, such as mature HDL particles, promote cholesterol efflux by multiple mechanisms
involving passive diffusion, interaction with SR-B1, and
the transport activities of ABCG1, ABCG4, and ABCA1.
Whether or not an HDL particle has activity for the
ABCA1 pathway probably depends on its ability to act as
a donor of lipid-free apolipoproteins that dissociate from
the particles (178, 201).
The ABCA1 pathway has broad specificity for multiple HDL apolipoproteins, including apolipoproteins AI,
AII, E, CI, CII, CIII, and AIV (226). These apolipoproteins
contain 11–22 amino acid repeats of amphipathic ␣-helices (249). 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 amphipathic ␣-helices in HDL apolipoproteins
fall into two major subclasses based on the distribution of
charged amino acids (Fig. 3). Class A helices, the most
common subclass, tend to cluster their positively charged
amino acids along the polar-nonpolar boundaries and the
negatively charged amino acids along the center of the
polar region (249). Type Y amphipathic ␣-helices have a
similar distribution pattern, except they have a positive
charge disrupting the cluster of negative charges on the
polar face (Fig. 3). Type Y helices have a higher lipid
FIG. 2. Models for ABCA1-mediated
cellular lipid trafficking and secretion.
Exocytosis: free cholesterol (FC) derived
from hydrolysis of esterified cholesterol
(EC) lipid droplets is assembled with
phospholipids (PL), perhaps in the Golgi
apparatus, to generate vesicles that translocate to plasma membrane domains containing ABCA1 (U-shaped structure). Lipids are transported across the plasma
membrane where they interact with apolipoproteins (squiggles) and are removed
from the cell, forming nascent HDL particles (disks). Retroendocytosis: apolipoproteins interact with ABCA1 or partner
proteins and are endocytosed with ABCA1
to intracellular deposits of C and PL. The
lipids are transported into the vesicle lumen where they interact with apolipoproteins, and the lipid-apolipoprotein complex is released from cells after the vesicle
fuses with the plasma membrane.
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286), consistent with phospholipids being the primary
substrate for ABCA1. Analysis of lipids removed by apolipoproteins implicates phosphatidylcholine as the major
phospholipid substrate (70, 166). There is evidence that
ABCA1 translocates phosphatidylserine to the exofacial
side of the plasma membrane (34, 233, 309), which was
proposed to account for ABCA1-mediated cellular apolipoprotein binding and cholesterol efflux (34). Another
study, however, suggests that the increased phosphatidylserine translocation associated with ABCA1 expression is
too small to account for the enhanced apolipoprotein
binding and cholesterol efflux (257). Moreover, there is no
selective enrichment of phosphatidylserine in the phospholipids removed by apolipoproteins (70, 166), implicating little interaction with phosphatidylserine-rich domains. Nevertheless, there is evidence that ABCA1 promotes engulfment of apoptotic cells by macrophages
(100) and generates microparticles that bleb from plasma
membranes (49, 166), two processes that may require
phosphatidylserine surfacing.
The broad substrate specificity of ABCA1 is consistent with targeting specific lipid domains for removal
from the cell. It is possible that ABCA1 can simultaneously transport several molecules, provided they are
associated with phosphatidylcholine. These could include
cholesterol and other lipophiles (e.g., ␣-tocopherol or
peptides) that accumulate in membrane domains accessible to ABCA1. Although ABCA1 substrates may be diverse, the most physiologically relevant of these are likely
to be cholesterol and phospholipids, because overloading
cells with cholesterol induces ABCA1 expression (see
below) and phospholipids are required cofactors for cholesterol transport.
ABCA1 FUNCTION AND PATHOBIOLOGY
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FIG. 3. Apolipoprotein amphipathic ␣-helices. Helical wheel projections of 18-amino-acid peptide analogs of
class A and class Y amphipathic ␣-helices (provided by
G. M. Anantharamaiah) and domain map of amphipathic
␣-helices in apoA-I (249). Segments represent the full
length of mature apoA-I, with amphipathic ␣-helices
numbered sequentially and indicated as either class A
(lighter) or class Y (darker) helices. The NH2-terminal
segment (left) is predicted to be nonhelical.
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The broad specificity for amphipathic ␣-helices implies that proteins other than apolipoproteins containing
this structural motif could remove cellular lipids by the
ABCA1 pathway. Indeed, it was shown that phospholipid
transfer protein (PLTP), which contains amphipathic
␣-helices, can interact with ABCA1 and remove cellular
cholesterol and phospholipids (209). Because of its low
lipid binding capacity, PLTP tends to transfer these lipids
to HDL rather than generate new lipoprotein particles.
PLTP plays important and diverse roles in lipoprotein
metabolism, including transferring phospholipids between lipoproteins, remodeling HDL to generate lipidpoor particles, and facilitating the production of triglyceride-rich apoB-containing particles in the liver (5, 123,
125, 126, 271). At physiological levels, PLTP may help
overcome some of its atherogenic effects by transferring
excess cholesterol from macrophages to HDL. Because of
its low lipid binding, however, high concentrations of
PLTP may actually block lipid removal from cells by
interfering with apolipoprotein interactions. These observations may partially explain why both deleting and hyperexpressing PLTP in mice increases atherosclerosis
(126, 273).
Serum amyloid A (SAA) also removes cellular lipids
by the ABCA1 pathway (258). SAA is an acute-phase
protein that is induced over 1,000-fold during inflammation (110). SAA mostly associates with HDL in the plasma.
It contains two tandem amphipathic ␣-helices that differ
in amino acid charge distribution from those in apolipoproteins. Although the function of SAA is unknown,
one activity may be to remove excess lipids through its
interactions with ABCA1. This may become necessary at
sites of inflammation where macrophages ingest cholesterol-rich membranes from apoptotic and necrotic cells.
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affinity than type A helices (86). Because of these novel
distributions of charged residues, apolipoproteins associate with lipid surfaces but can freely exchange between
surfaces through the aqueous environment. These properties also allow lipid free apolipoproteins to assemble
phospholipids and free cholesterol to generate nascent
HDL particles.
The most abundant apolipoprotein in HDL is apoA-I,
which comprises ⬃70% of the total HDL protein content.
ApoA-I contains eight 22-amino acid and two 11-amino
acid tandem amphipathic ␣-helical domains (Fig. 3). Studies of synthetic peptides corresponding to each of these
helices showed that helices 1 and 10 have the greatest
affinity for phospholipids (86, 277). These peptides, however, failed to mediate ABCA1-dependent cholesterol efflux unless they were covalently linked to the 11-mer helix
9 (189). This linkage produced a linear array of acidic
amino acids along the polar face of the helices, suggesting
that this may be an important apoA-I structural determinant for lipid removal by the ABCA1 pathway (189). The
importance of the COOH-terminal helices in this process
is supported by studies showing that truncation mutants
of apoA-I lacking the 10th helix were unable to remove
cholesterol from cells by the ABCA1 pathway (215).
A synthetic 18-amino acid peptide that is an analog of
class A amphipathic ␣-helices (Fig. 3, top left) can mimic
apoA-I in removing cholesterol and phospholipids by the
ABCA1 pathway. A dimer of this peptide is more efficacious (176, 306), suggesting cooperativity between tandem helices. These studies imply that the amphipathic
␣-helix is the major structural motif required for removing
ABCA1-transported lipids. Interestingly, the D-isomer of
the 18-mer ␣-helix is just as active as the L-isomer (9, 227),
suggesting that there are no stereoselective requirements
for these peptides to interact with ABCA1 lipid transport.
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JOHN F. ORAM AND JAY W. HEINECKE
E. Apolipoprotein Binding
F. Lipid Transport Model
Although the structure of ABCA1 has not been characterized, electron microscopy and X-ray crystallography
FIG. 4. Model for the lipid translocase
activity of ABCA1. Excess cellular cholesterol along with phospholipids accumulates within domains of the cytosolic leaflet of membranes and is laterally transported into the open chamber (top left).
ATP binding dimerizes the NBDs and
closes the chamber, and the trapped lipids
are flipped to the outer membrane leaflet
(step A). The hydrolysis of ATP by the
NBDs forms an ADP-bound intermediate
that changes the conformation of the
transmembrane domains, opening the
chamber at the membrane outer leaflet
(step B). Lipids are extruded from the
chamber into cholesterol-rich domains on
the cell surface, where they are removed
by apolipoproteins to form nascent HDL
particles (step C). The structure of the
ABCA1 chamber reverts back to its substrate uptake conformation after ADP dissociates from the NBDs (step D).
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Covalent cross-linking studies revealed that apolipoproteins bind directly to ABCA1 with saturability and high affinity (Kd ⬍10⫺7 M) (45, 72). This binding is temperature
sensitive and readily reversible. The apolipoprotein binding
sites on ABCA1 have a broad specificity for multiple HDL
apolipoproteins, including apos A-I, A-II, C-I, C-II, and C-III
(72). These sites also recognize the 18-mer synthetic amphipathic ␣-helix (72) and PLTP (209). Thus the broad specificity of the ABCA1 binding sites closely mirrors the ABCA1dependent lipid transport activity of the acceptors. These
binding sites have not yet been identified, but their loose
specificity for amphipathic ␣-helices suggests that they may
be rich in hydrophobic amino acids.
Mutational analyses have uncovered a dissociation
between the lipid transport activity of ABCA1 and its
apolipoprotein binding activity. Nearly all missense mutations in ABCA1 that impair lipid efflux to apolipoproteins also impair apolipoprotein binding to ABCA1 (73).
One substitution mutation (W590S), however, severely
reduces apolipoprotein-mediated lipid efflux without having much effect on apolipoprotein binding (73). These
results imply that apolipoprotein binding to ABCA1 is
essential but not sufficient for removing lipids. As discussed below, the intrinsic lipid transport activity of
ABCA1 and its apolipoprotein binding activity can also be
regulated independently. It is therefore likely that these
two activities depend on different properties of ABCA1.
of other ABC transporters have generated molecular models that may apply to ABCA1. The two most studied ABC
structures belong to mammalian P-glycoprotein (234,
235), which extrudes a variety of lipophilic compounds
from cells, and bacterial/pathogenic MsbA (35, 36), which
translocates lipids from the inner to outer membrane
leaflets. Despite some disagreement about mechanisms
involved, the consensus of these analyses suggests 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. This involves a series of conformational
changes in the ABC protein that is probably driven by the
NBD domains (Fig. 4) (35, 235).
These structural studies suggest the following model
for the ABCA1 pathway. Excess cellular cholesterol along
with phospholipids accumulate within domains of the
cytosolic leaflet of the plasma membrane or intracellular
vesicle membranes (Fig. 4, top left). This cholesterol is
not accessible to apolipoproteins and therefore must be
translocated to the cell surface or into the vesicle lumen
for removal. These lipid domains may assemble in the
vicinity of ABCA1 molecules, or ABCA1 may migrate to
these domains after they are formed. Other lipophilic
molecules may also accumulate in these domains.
The MsbA model predicts that the transmembrane
chamber of ABCA1 is initially open at the bottom (Fig. 4,
top left) (35, 36). Lipids in the inner membrane leaflet are
laterally transported into the chamber by a process that is
facilitated by high-affinity phospholipid binding sites. This
phospholipid recognition induces ATP binding to the
NBDs, which promotes their dimerization and thus closes
ABCA1 FUNCTION AND PATHOBIOLOGY
III. REGULATION
A. Expression
1. Transcription
As expected for a transporter that mediates secretion
of excess cellular cholesterol, transcription of ABCA1 is
markedly induced by overloading cells with cholesterol.
This induction occurs exclusively through activation of
the nuclear receptors liver X receptor (LXR␣ and/or
LXR␤) and retinoid X receptor (RXR) (51, 247). LXR and
RXR form obligate heterodimers that preferentially bind
to response elements within the ABCA1 gene promoter
and the first intron. LXRs and RXRs bind to and are
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activated by oxysterols and retinoic acid, respectively
(230). Binding of either one or both ligands can activate
transcription. Treatment of cells with either an oxysterol
or 9-cis-retinoic acid induces ABCA1, but their combined
treatment has marked synergistic effects (51, 247). The
LXR␣ gene promoter in human macrophages contains a
LXR response element (146, 297), indicating that LXR␣
can autoregulate its own expression. This would serve to
amplify the effects of oxysterols on the ABCA1 lipid efflux
pathway.
Because uptake of nonoxidized cholesterol by cells
increases ABCA1 expression, cholesterol must be converted to oxysterols before inducing ABCA1. The most
potent LXR ligands contain a single stereoselective oxygen on the side chain that functions as a hydrogen bond
acceptor (121). It is believed that 22-hydroxycholesterol,
24-hydroxycholesterol, and 24,25-epoxycholesterol are
the major naturally occurring liver LXR ligands (121).
Most oxysterols are generated by cytochrome P-450 enzymes that are particularly prevalent in the liver and play
a role in bile acid metabolism. One of these enzymes,
sterol 27-hydroxylase (Cyp27), is broadly distributed in
various tissues and cell types, including macrophages,
suggesting that 27-hydroxycholesterol is the major LXR
ligand in macrophages and other peripheral cells (80).
Consistent with this idea is the accelerated atherosclerosis that is associated with cerebrotendinous xanthomatosis, a rare inherited disease characterized by a lack of
Cyp27 (124). Recent studies with mouse models lacking
or overexpressing Cyp27, however, suggest that 27-hydroxycholesterol has little impact on whole body cholesterol homeostasis (175).
Lipid metabolites other than sterols can modulate
ABCA1 expression by the LXR system (Table 1). Polyunsaturated fatty acids act as antagonists to oxysterol binding to response elements in the LXR␣ gene (214), potentially interfering with induction of ABCA1 by sterols
(272). Geranylgeranyl pyrophosphate (GGPP), a product
of the mevalonate pathway that isoprenylates proteins,
was shown to suppress LXR-induced ABCA1 synthesis by
two mechanisms: as an antagonist of the interaction of
LXR with its nuclear coactivator SRC-1 and as an activator of Rho GTP-binding proteins (82). This second mechanism might alter sterol trafficking in cells, reducing their
availability as ligands for LXR. Activators of peroxisome
proliferator activating nuclear receptors (PPARs) also enhance ABCA1 transcription in some cells. PPAR␥ activators stimulate cholesterol efflux from cells by activating
transcription of the LXR␣ gene, which in turn induces
ABCA1 transcription (37, 41). Thyroid hormone receptor
was reported to suppress ABCA1 transcription by forming a complex with RXR that competes for LXR/RXR
binding to its response elements (115).
ABCA1 transcription is also regulated by factors independent of LXR/RXR (Table 1). Membrane-permeable
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the chamber (Fig. 4, step A). The interactions of phospholipid polar head groups with charged amino acids in the
chamber flips the trapped lipids to the outer leaflet. The
hydrolysis of ATP by the NBDs forms an ADP-bound
intermediate that changes the conformation of the transmembrane domains, opening the chamber at the membrane outer leaflet (Fig. 4, step B). Because of a decreased
affinity for phospholipid binding, lipids are extruded from
the chamber into cholesterol-rich domains on the cell
surface, where they are removed by apolipoproteins to
form nascent HDL particles (Fig. 4, step C). The structure
of the ABCA1 chamber reverts back to its substrate uptake conformation after ADP dissociates from the NBDs
(Fig. 4, step D). Although this is a plausible model for
ABCA1 function, more direct evidence is needed to confirm that it actually applies to this transporter.
The removal of lipids by apolipoproteins appears to
involve a two-step process, whereby apolipoproteins first
bind to ABCA1 and then solubilize the ABCA1-transported lipids (Fig. 4, step C) (45). Apolipoprotein binding
to ABCA1 is not required for lipid flippase activity, as
ABCA1 translocates cholesterol to the cell surface in the
absence of apolipoproteins (276). This binding may serve
to target apolipoproteins to the lipid domains formed by
ABCA1. It might also promote extrusion of lipids from the
open chamber by dissociating phospholipids from their
binding sites.
There is evidence that ABCA1 forms oligomers in
both intracellular membranes and the plasma membrane
and that the homotetramer is the major functional unit
(55). It was postulated that the interaction of apolipoproteins with each of these units may be responsible for
generation of nascent HDL particles containing four or
more apolipoprotein molecules per particle. Binding of
apolipoproteins to ABCA1 does not appear to be required
for its oligomerization. The oligomeric structure of functional ABCA1 is consistent with what has been observed
for other ABC transporters (225, 236).
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TABLE
JOHN F. ORAM AND JAY W. HEINECKE
1.
Regulation of ABCA1 expression
Effector
ABCA1
Mechanism
Reference Nos.
LXR␣, LXR␤
RXR
LXR␣, LXR␤
ggPP, Rho
PPAR␥
Hormone receptor
cAMP
Calcium?
ZNF202
Sp1
Sp3
USF1/USF2/Fra2
?
?
?
SREBP 2
⫹
⫹
⫺
⫺
⫹
⫺
⫹
⫹
⫺
⫹
⫺
⫺
⫹
⫺
⫹
⫺
⫹ ABCA1 transcription
⫹ ABCA1 transcription
Antagonizes sterols
⫺ LXR activity
⫹ LXR transcription
⫺LXR/RXR activity
⫹ ABCA1 transcription
⫹ ABCA1 transcription
⫺ ABCA1 transcription
⫹ ABCA1 transcription
Antagonizes Sp1
⫺ ABCA1 transcription
⫹ ABCA1 transcription
Antagonizes IFN-␥
⫹ ABCA1 transcription
⫺ ABCA1 transcription
51, 245
51, 245
212, 270
82
37, 41
114
23, 204
258
221
146
146
306
214
10, 214
146
307
?
PLD2
Proteosomes
?
␣1-Syntrophin
Syntaxin 13
?
?
⫹
⫺
⫺
⫺
⫹
⫹
⫹
⫺
⫺ ABCA1 degradation
⫹ABCA1 degradation
⫹ABCA1 degradation
⫹ABCA1 degradation
ABCA1 trafficking?
ABCA1 trafficking?
ABCA1 trafficking
ABCA1 trafficking
9, 282
288–290
66
218
182
14
297
149
IFN, interferon; TGF, transforming growth factor; LXR, liver X receptor; RXR, retinoid X receptor; PPAR, peroxisome proliferator activating
nuclear receptor.
analogs of cAMP (23, 206) and inhibitors of cAMP-specific
phosphodiesterase 4 (162) stimulate Abca1 transcription
in murine macrophages by unknown mechanisms. The
calcium channel blocker verapamil can also enhance
ABCA1 transcription by an LXR-independent process
(260). The ABCA1 gene promoter contains other transcriptional response elements that are potential sites of
regulation (148, 223, 307), some of which may influence
constitutive and tissue-specific expression of ABCA1. Cytokines such as interferon-␥ (216), transforming growth
factor ␤1 (10), and oncostatin M (148) have been reported
to modulate ABCA1 transcription in cultured macrophages and hepatoma cells. Sterol regulatory element
binding protein 2, a transcription factor that regulates
sterol synthesis, appears to interact with the ABCA1 promoter in vascular endothelial cells and to suppress
ABCA1 transcription (308), thus providing an additional
mechanism for suppressing cholesterol efflux when cells
are sterol depleted.
2. Protein stability
The only posttranscriptional processes so far identified that affect ABCA1 expression involve modulation of
ABCA1 protein stability (Table 1). 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) (290). The rapid protein turnover is largely due to
Physiol Rev • VOL
a sequence at amino acids 1283–1306 in the first intracellular loop that is enriched in proline-glutamate-serinethreonine (PEST motif) (283). Phosphorylation of T1286
and T1305 in this motif (Fig. 5) promotes ABCA1 proteolysis by an unknown member of the calpain protease
family (173, 283). There are several metabolic factors that
modulate the rate of ABCA1 protein degradation by either
this calpain system or other processes.
A) APOLIPOPROTEINS. The interaction of apolipoproteins
with ABCA1-expressing cells dramatically reduces the
rate of ABCA1 degradation (9, 283). This acts as a feedback mechanism to increase ABCA1 levels when acceptors for lipid transport are available. Studies have uncovered two possible mechanisms that might contribute to
this protein stabilization. First, the cellular interactions of
apolipoproteins interfere with the phosphorylation of the
PEST motif, reducing calpain-mediated proteolysis of
ABCA1 (173, 283, 287). Second, the removal of membrane
sphingomyelin by apolipoproteins activates phosphatidylcholine phospholipase C, which signals phosphorylation
of ABCA1 at a site that stabilizes the protein (305). It is
unknown if either or both of these mechanisms require
apolipoprotein binding to ABCA1.
B) FREE FATTY ACIDS. Unsaturated free fatty acids directly
destabilize ABCA1 protein in cultured cells (289, 290).
When ABCA1 is induced by LXR-independent mechanisms, mono-, di-, and polyunsaturated fatty acids in-
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Transcription
Sterols
Retinoids
Polyunsaturated fatty acids
GeranylgeranylPP
Thiazolidinediones
Thyroid hormone
?
Verapamil
?
?
?
?
IFN-␥
TGF-␤
Oncostatin M
EC sterol depletion
Posttranscription
Apolipoproteins
Unsaturated fatty acids
Free cholesterol
Reactive carbonyls
?
?
Ceramide
Cyclosporin
Mediator
1351
ABCA1 FUNCTION AND PATHOBIOLOGY
crease the rate of ABCA1 protein degradation (290). In
contrast, saturated fatty acids have no effect on ABCA1
turnover in these cells. However, if ABCA1 is induced by
LXR ligands, the saturated fatty acids palmitate and stearate also destabilize ABCA1 (289). This is because one of
the other genes induced by LXR encodes an enzyme
called stearoyl-CoA desaturase, which converts these two
saturated fatty acids to their monounsaturated derivatives, palmitoleate and oleate (289). Thus, in most cholesterol-loaded cells in vivo, where ABCA1 is induced by
LXR-activating sterols, it is likely that exposure to both
saturated and unsaturated fatty acids impair the ABCA1
cholesterol secretion pathway by reducing ABCA1 levels.
The effects of fatty acids on ABCA1 stability appear
to be mediated by a signaling pathway involving activation of phospholipase D2 and phosphorylation of ABCA1
(291). The biologic reason for this cross-regulation by
different lipid classes is unclear, but it is possible that
suppressing ABCA1-mediated lipid secretion by unsaturated fatty acids plays a physiological role in cellular lipid
homeostasis, perhaps to retain excess cholesterol as a
reservoir for membrane synthesis. This regulation, however, may have pathological consequences. Type 2 diabetes and the metabolic syndrome are characterized by
elevated fatty acids, low plasma HDL levels, and prevalent
CVD (19, 88). Palmitate and oleate, the two most common
fatty acids, destabilize ABCA1 over a fatty acid-to-albumin
molar ratio within the range observed for subjects with
these disorders (289, 290). It is possible that impaired
ABCA1-mediated cholesterol secretion from cells contributes to the low plasma HDL levels and enhanced atherosclerosis in these subjects.
C) FREE CHOLESTEROL. Loading cultured macrophages
with cholesterol in the presence of a drug that inhibits
Physiol Rev • VOL
cholesterol esterification induces apoptosis, which is triggered by the accumulation of free cholesterol in the endoplasmic reticulum (67). This condition also destabilizes
ABCA1 protein, possibly by enhancing degradation by
proteosomes (66). Thus an impaired ability of ABCA1 to
remove lipids from macrophages may potentiate the damaging effects of free cholesterol. Such a mechanism could
contribute to progression of atherosclerosis, as macrophages progressively accumulate large amounts of free
cholesterol in advanced lesions.
D) REACTIVE CARBONYLS. Treatment of cultured macrophages with the reactive carbonyl species glyoxal and
glycoaldehyde acutely and severely impair the ABCA1
pathway, presumably by directly damaging ABCA1 protein (220). These carbonyls are generated during glucose
metabolism and protein glycoxidation and form advanced
glycated end products (AGEs) on tissue proteins (15, 28,
89, 267, 300). AGEs accumulate during aging, and their
formation is enhanced by diabetes. In addition to glycoxidation, activated phagocytes can generate glycoaldehyde
from amino acids using myeloperoxidase (7). Thus the
inflammation that underlies multiple disorders including
diabetes is likely to produce carbonyl stress in tissues and
impair the ABCA1 pathway. This could be another mechanism that contributes to the increased CVD associated
with these metabolic disorders.
3. Protein trafficking
Modulation of ABCA1 trafficking could have important influences on ABCA1 protein levels and function
(Table 1). ABCA1 recycles rapidly between the plasma
membrane and late endosomal/lysosomal compartments
(193, 194), which may play a role in both lipid transport
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FIG. 5. Known phosphorylation sites in
ABCA1. Approximate sights of phosphorylated threonines in the PEST sequence that
mediate ABCA1 degradation by calpain (triangles), of serines phosphorylated by protein kinase A in the NBDs that are required for optimum lipid translocase activity (diamonds),
and of threonines and serine phosphorylated
by protein kinase CK2 that attenuate lipid
transport and apolipoprotein binding acitivities (pentagons).
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JOHN F. ORAM AND JAY W. HEINECKE
TABLE
2.
binding protein (14). Silencing of syntaxin 13 with siRNA
reduced ABCA1 protein levels and lipid efflux to HDL and
apoA-I without affecting ABCA1 mRNA levels (14). Thus
syntaxin 13 appears to stabilize ABCA1 protein, probably
by modulating its vesicular trafficking. In addition to endosomes, macrophage phagosomes also appear to contain syntaxin 13, raising the possibility that phagocytotic
vesicles play a role in processing ABCA1.
Several compounds have been described that appear
to affect ABCA1 levels or activity through their effects on
ABCA1 trafficking. Ceramide was shown to enhance cholesterol efflux to apolipoproteins by increasing the cell
surface content of ABCA1 (298). In contrast, cyclosporin
A was reported to inhibit ABCA1-dependent lipid efflux
by trapping ABCA1 on the cell surface where it lost
activity (156). These studies show that agents that alter
the trafficking patterns of ABCA1 can have significant
effects on its cellular content and activity.
B. Activity
1. Signaling pathways
The lipid transport and apolipoprotein binding activities of ABCA1 are regulated by several signaling pathways that have no or little effect on ABCA1 expression
(Table 2). Most of these pathways affect ABCA1 by direct
phosphorylation. Several protein kinases have been described that modulate ABCA1 lipid transport and/or apolipoprotein binding activity. These signaling pathways can
either increase or decrease different aspects of ABCA1
activity and thus coordinate its overall function.
A) PROTEIN KINASE A. Activation of protein kinase A (PKA)
by cAMP is required for optimum lipid transport activity
of ABCA1 (248, 264). Mutational studies and in vitro kinase activity assays showed that this occurs by PKAmediated phosphorylation of serines 1042 and 2054 lo-
Regulation of ABCA1 activity
Effector
Signaling
Apolipoproteins?
Cytokines?
?
Apolipoproteins
Apolipoproteins
Partner proteins
?
?
?
Substrate
trafficking
Cholesterol?
Apolipoproteins
?
Mediator
ABCA1
Mechanism
Reference Nos.
Protein kinase A
⫹Lipid transport
ABCA1 phosphorylation
96, 97, 246, 262
Protein kinase CK2
ABCA1 phosphorylation
231
Janis kinase 2
Protein kinase C
⫺Lipid transport
⫺Apo binding
⫹Apo binding
⫹Lipid transport
?
ABCA1 phosphorylation?
262
158
Cdc42
FADD
?
⫹Lipid transport
⫹Lipid transport
⫹Apo binding
ABCA1 binding
ABCA1 binding
ABCA1-VFVNFA binding
57, 107, 195, 268
30
74
ARL7
Protein kinase C
NPC1
⫹Cholesterol transport
⫹Cholesterol transport
⫹Cholesterol transport
Cholesterol trafficking
Cholesterol trafficking
Cholesterol trafficking
65
303
42
Physiol Rev • VOL
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and protein processing. ABCA1 is selectively expressed
on the basolateral membranes of cultured intestinal cells
(185, 200), gallbladder epithelial cells (151), brain capillary endothelial cells (218), alveolar type II cells (312),
and hepatocytes (192), indicating the presence of factors
that target ABCA1 to specific membranes in polarized
cells. There is emerging evidence that the interaction of
proteins with the COOH-terminal domain may be involved
in directing intracellular trafficking of ABCA1.
The COOH terminus of ABCA1 contains a ESTV motif
that conforms to the consensus sequence for binding to
PDZ domain-containing proteins (74), a diverse group of
proteins that form multimeric complexes that often mediate cytoskeleton interactions and protein trafficking
(139). Yeast two-hybrid screens identified three PDZ proteins (␣1- and ␤2-syntrophin and Lin7) that interact with
the COOH-terminal domain of ABCA1 (29, 184). Overexpressing ␣-syntrophin in cells stabilized ABCA1 and enhanced cholesterol efflux (184), suggesting that its interaction with ABCA1 is important for optimum function.
When a mutant for ABCA1 lacking the PDZ binding domain was modestly overexpressed in cells, cholesterol
efflux was less than half that seen with cells expressing a
similar amount of wild-type ABCA1 (74). However, when
cells were forced to express high levels of this mutant,
there was no impairment of cholesterol efflux. Thus it
appears that interactions of PDZ proteins with ABCA1
have modest effects on its function but are not essential
for activity. The role of these interactions in trafficking of
ABCA1 to membranes in polarized cells has not been
explored in detail.
Intracellular protein trafficking often involves the fusion of transport vesicles, which is mediated by a group of
vesicle membrane receptors called SNAREs, including the
syntaxin family of proteins. Screening macrophages for
syntaxins that are increased in response to cholesterol
loading led to the identity of syntaxin 13 as an ABCA1
ABCA1 FUNCTION AND PATHOBIOLOGY
Physiol Rev • VOL
most of these receptors. JAK2 also plays a role in modulating ABCA1 activity. A JAK2-specific inhibitor reduces
apoA-I-mediated lipid transport and apoA-I binding to
ABCA1, and mutant cells lacking JAK2 have a severely
impaired ABCA1 pathway (264). In contrast to PKA,
which regulates the lipid transport but not apolipoprotein
binding activity of ABCA1, JAK2 is required for apolipoprotein binding to ABCA1 but has little effect on the
intrinsic cholesterol flippase activity (264). These studies
show that the lipid transport and apolipoprotein binding
activities of ABCA1 can be regulated independently by
different signaling processes.
The interaction of apoA-I with ABCA1-expressing
cells acutely stimulates autophosphorylation of JAK2
(264), generating 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. It is unknown if the
initiating step in this process is mediated by binding of
apolipoproteins to ABCA1 or to other proteins, or
whether the JAK2-targeted protein is ABCA1 or a partner
protein.
D) PROTEIN KINASE C. In addition to the possibility that
phosphorylation of ABCA1 by protein kinase C (PKC)
helps stabilize the protein, there is circumstantial evidence that PKC may play a role in modulating the lipid
transport activity of ABCA1. Before the discovery of
ABCA1, several studies showed that inhibition or activation of PKCs respectively decreased or increased cholesterol efflux from cells to HDL or purified apoA-I (160, 179,
266, 282), implicating PKCs as modulators of ABCA1 activity. More recent evidence suggested that activation of
phospholipase C and D may be critical for apoA-I-mediated cellular cholesterol efflux (99, 281). However, this
also appeared to be the case in cells with defective
ABCA1 (99), suggesting that it may not directly involve
this transporter. Moreover, short-term treatment of
ABCA1-transfected cells with a broad-spectrum PKC inhibitor was shown to have no effect on apoA-I-mediated
cholesterol or phospholipid efflux (264). It is possible that
PKCs do not directly activate ABCA1 but modulate trafficking of lipid substrates to ABCA1 (see below).
2. Partner proteins
There is growing evidence that ABCA1 activity is
modulated by the interaction of a diverse group of proteins (Table 2). ABCA1 was coimmunoprecipitated with
Cdc42 (270), a member of the RhoGTPase family that
forms complexes with proteins that control the cytoskeletal architecture and vesicular transport (262). This interaction may cause the changes in cell morphology associated with under- or overexpressing ABCA1 (57, 270).
Moreover, forced expression of Cdc42 was shown to en-
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cated in the NBDs (Fig. 5) (248). Mutation of serine 1042
alone did not affect ABCA1 activity, suggesting that phosphorylation of serine in NBD-2 has the greatest impact.
Suppressing this phosphorylation severely reduced lipid
transport to apolipoproteins without altering apolipoprotein binding to ABCA1-expressing cells or to ABCA1 (248,
264). Thus the PKA-mediated phosphorylation of ABCA1
appears to be necessary for optimum intrinsic lipid transport activity but not for apolipoprotein binding activity.
Although PKA-mediated phosphorylation of ABCA1
is required for activity, the importance of this signaling
pathway as a physiological modulator of ABCA1 is unclear. Some studies have shown that incubating cells with
cAMP analogs had no stimulatory effect on ABCA1 activity or phosphorylation, even though PKA inhibitors could
reduce these processes, consistent with the idea that the
intracellular cAMP content is already saturating for its
effects on ABCA1 (207, 264). Other studies, however, have
shown that increasing the cellular cAMP content enhances ABCA1 activity in association with increased
ABCA1 phosphorylation (97, 98). Moreover, the interaction of apoA-I with ABCA1-expressing cells was reported
to increase the cellular cAMP content and ABCA1 phosphorylation (98). The reason for these discrepancies is
unknown, but it may reflect difference in cell lines and
culture conditions. In support of this idea is a study
showing that immortalizing primary fibroblasts increased
the responsiveness of the ABCA1 pathway to a cAMP
analog (207).
B) PROTEIN KINASE CK2. Protein kinase 2 or CK2 is a serine/
threonine kinase that plays a role in multiple processes
related to cell survival and transformation (165, 243).
Studies using recombinant peptides spanning the intracellular domains of ABCA1 showed that CK2 phosphorylates
ABCA1 at threonines 1242 and 1243 and serine 1255,
which are downstream from NBD-1 (Fig. 5) (233). Sitedirected mutagenesis of these domains prevented CK2mediated ABCA1 phosphorylation and enhanced lipid
flipping, apolipoprotein binding to cells, and apolipoprotein-mediated lipid efflux (233). Thus CK2 acts as a downregulator of ABCA1 lipid transport and apolipoprotein
binding activities. Interestingly, CK2-mediated phosphorylation of a chicken homeoprotein called Engrailed 2
inhibits its secretion from cells (170). Although transported in vesicles and secreted, Engrailed 2 lacks a classic
signal sequence. A similar secretion mechanism has been
described for interleukin-1␤, a reported substrate for
ABCA1 (101, 313). These observations are consistent with
an attenuating role of CK2 in ABCA1-dependent secretion
of substrates that are important for normal cell function
and viability.
C) JANUS KINASE 2. Janus kinase 2 (JAK2) is a tyrosine
kinase that is activated by over half of the cytokine/
hematopoietin superfamily of receptors (137). Activation
of JAK2 is the initiating step in downstream signaling for
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JOHN F. ORAM AND JAY W. HEINECKE
3. Substrate trafficking
The activity of the ABCA1 pathway is influenced by
factors that control intracellular trafficking of lipids (Table 2). Cholesterol, phospholipids, and other lipophiles
are likely to be transported between cellular compartments in vesicular membranes. ADP-ribosylation factors
(ARFs) and ARF-like proteins (ARLs) are Ras-related
small GTPases that control the vesicle budding involved
in vesicular transport pathways. One of these ARLs
(ARL7) was shown to be induced by cholesterol loading
of macrophages and by LXR/RXR agonists (65). Immunofluorescent studies suggested that ARL plays a role in
vesicular transport between a perinuclear compartment
and the plasma membrane. Expression of native and dominant-active ARL7 stimulated cholesterol efflux from cells
by the ABCA1 pathway (65). These observations suggest
that ARL7 is involved in trafficking of cholesterol from
intracellular compartments to plasma membrane domains
containing ABCA1, although they do not exclude the possibility that these ARL7-containing vesicles target ABCA1
to lipid domains.
Trafficking of lipid substrates to ABCA1 may also be
mediated by signaling processes elicited by the interaction of apolipoproteins with ABCA1-expressing cells. The
ability of apolipoproteins to remove cholesterol selectively from sites of cholesterol esterification has been
reported to involve activation of PKC by apolipoproteins
(304).
Physiol Rev • VOL
Disorders that affect intracellular cholesterol trafficking have an impact on the ABCA1 pathway. NiemannPick type C (NPC) disease is a neurodegenerative disorder characterized by impaired intracellular lipid trafficking and accumulation of free cholesterol in late
endosomes/lysosomes (84, 144, 195, 222). This is due to
mutations in the gene for NPC1, which mediates transport
of lipoprotein-derived cholesterol from these intracellular
compartments to the Golgi apparatus, endoplasmic reticulum, and plasma membrane. Cells lacking NPC1 have
below normal levels of ABCA1 expression and activity
(42), consistent with an impaired transport of intracellular cholesterol to sites that regulate ABCA1 transcription
and to membrane domains targeted for efflux. This impaired ABCA1 pathway may explain why patients with
NPC have low plasma HDL levels and an overaccumulation of cellular cholesterol (42).
IV. IN VIVO FUNCTIONS
ABCA1 is widely expressed throughout animal tissues where it may have multiple and diverse functions. In
humans, ABCA1 mRNA was reported to be most abundant in liver, placenta, small intestine, and lung (138). In
the baboon, ABCA1 mRNA was shown to be abundant in
tissues containing inflammatory cells and lymphocytes,
but it was also detected in noninflammatory cells in the
kidney, medulla, testis, and brain (149). In mice, ABCA1
mRNA was reported to be most abundant in liver, kidney,
adrenal, heart, bladder, testis, and brain (296). Interestingly, measurements of ABCA1 protein levels in tissues
showed discordance with mRNA abundance, in that some
tissues with high mRNA levels (kidney, heart, bladder,
and brain) had relatively low protein levels (296). These
observations are consistent with the possibility that posttranscriptional regulation plays a major role in tissue
expression of ABCA1.
Tissue culture studies predict that macrophage-rich
tissues would have relatively high levels of ABCA1. As
scavenger cells, macrophages ingest modified lipoproteins and damaged cell membranes and thus can accumulate large amounts of cholesterol, an inducer of ABCA1.
Indeed, ABCA1 mRNA levels were shown to be higher in
cholesterol-loaded cultured human macrophages than in
any human tissues (138). ABCA1 is also highly expressed
in the liver, where it is upregulated when mice are fed a
high-cholesterol diet (296). It is therefore predictable that
hepatic ABCA1 would make an important contribution to
whole body lipoprotein metabolism. Current knowledge
about the physiological role of ABCA1 in vivo is based
largely on studies of human genetic disorders, mouse
genetic models, and cultured tissue-specific cells.
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hance apoA-I-mediated cholesterol efflux, whereas expression of dominant negative Cdc42 impaired this efflux,
consistent with a role of Cdc42 in modulating ABCA1
function (108, 197).
Immunoprecipitation studies also identified Fas-associated death domain protein (FADD) as an ABCA1 interacting protein (30). Blocking this interaction impaired
apolipoprotein-mediated phospholipid efflux. The biological significance of the FADD/ABCA1 association is unclear, as FADD is mainly involved in death receptorinduced apoptosis. These findings raise the possibility
that ABCA1 has an antiapoptotic function, perhaps related to its ability to extrude lipophilic molecules from
cells.
It is likely that additional proteins will be discovered
that interact with ABCA1 and modulate activity. The
COOH-terminal region of ABCA1 contains a highly conserved VFVNFA motif that is required for activity (74).
Mutations in this motif have no effect on ABCA1 trafficking but severely impair its apoA-I interactions and lipid
efflux. Peptide competition experiments suggest that this
motif promotes the interaction of ABCA1 with an unknown cellular protein that is a component of the active
complex (74).
ABCA1 FUNCTION AND PATHOBIOLOGY
A. HDL Production
1. Genetic variations
Physiol Rev • VOL
with moderately reduced HDL levels, which is more typical of Tangier disease heterozygotes (255). Taken together, these observations are consistent with ABCA1
being a major determinant of plasma HDL levels in humans.
The role of ABCA1 as a modulator of HDL levels and
size was supported by two independent reports that measured cholesterol efflux from cells cultured from Tangier
disease heterozygotes. Although these patients as a group
have approximately half normal plasma HDL levels, there
is a wide variation among patients (255). The type of
ABCA1 mutation may have some influence on the relative
activity of the ABCA1 pathway, since truncation mutants
may form dominant-negative interactions with the wildtype allele (255). This range in activity allowed for comparisons of apoA-I-mediated cholesterol efflux from skin
fibroblasts cultured from these patients with their plasma
HDL levels and particle size. Both studies showed a significant correlation between ABCA1 activity in their cultured skin fibroblasts and the level and size of plasma
HDL particles (25, 47). Thus, at least among this subject
group, the intrinsic activity of the ABCA1 pathway is a
major determinant of plasma HDL cholesterol levels.
SNP analyses have also identified over 20 common
polymorphisms (⬎1% allelic frequency) in the coding,
promoter, and 5⬘-UTR regions of ABCA1 (48, 78, 255).
Several of these are associated with either low or high
plasma HDL levels. The most studied of these SNPs is the
R219K variant, with the K allele being associated with
higher levels of HDL (255). V771M and V825I SNPs have
also been reported to be associated with increased HDL
levels, whereas R1587K is associated with low levels of
HDL (78, 255). Although the frequencies vary between
groups, all of these more common SNPs were present in
individuals having both high and low HDL levels, suggesting that they do not have a strong phenotypic effect.
2. Animal models
Studies of animal models have provided additional
evidence that ABCA1 is a major determinant of plasma
HDL levels. The only naturally occurring animal model of
Tangier disease is the Wisconsin Hypoalpha Mutant
(WHAM) chicken. ABCA1 in these chickens has a missense mutation near the NH2 terminus that produces a
defective protein (13). Like Tangier patients, the WHAM
chicken hypercatabolizes apoA-I and accumulates cholesteryl esters in tissues, particularly in hepatic parenchymal and intestinal epithelial cells. Targeted disruption of
the Abca1 gene in mice produces a phenotype similar to
that of human Tangier disease (4, 174, 211), including an
HDL deficiency and accumulation of sterols in some tissues. Conversely, overexpressing ABCA1 in mice elevates
plasma HDL levels (131, 256, 294).
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Mutations in ABCA1 can cause an autosomal recessive genetic disorder called Tangier disease, which is
characterized by very low levels of plasma HDL and deposition of sterols in tissue macrophages (11). Tangier
disease was first identified in the 1960s as an HDL deficiency syndrome affecting families from Tangier Island in
the Chesapeake Bay, United States of America (77). It was
discovered in the mid 1990s that the ability of purified
apoA-I to remove cholesterol and phospholipids from
these cells was severely impaired (75). In 1999, four laboratories independently identified the defective Tangier
disease gene as ABCA1 (21, 24, 150, 239).
Over 70 mutations in ABCA1 have been identified in
subjects with low plasma HDL levels, nearly one-third of
which are missense mutations (48, 78, 255). Although
these mutations occur throughout the gene, they tend to
cluster in the extracellular loops, the NBD domains, and
the COOH-terminal region.
The functional impact of a small subset of the missense mutations has been studied in cell culture. When
expressed in cells, most of these mutants appear in the
plasma membrane but have severely impaired lipid transport and apolipoprotein binding activities (73). Some
studies have suggested that ABCA1 proteins with substitution mutations Q597R and R587W in the first extracellular loop do not localize to the plasma membrane (232,
263), but other studies have contradicted these findings
(73, 150). Missense mutations in the second extracellular
loop and in the ninth membrane-spanning domain were
reported to prevent ABCA1 trafficking to the plasma
membrane (6). Only one mutant (W590S) has been described that has near-normal apolipoprotein binding activity but defective lipid transport (73).
The initial loss-of-function mutations in ABCA1 were
discovered in case reports and family studies. More recently, rare mutations were identified by screening
ABCA1 from subjects with low plasma HDL levels for
single nucleotide polymorphisms (SNPs) (48, 78, 255).
Most of the identified rare alleles (mutations) were absent
in populations of subjects with high HDL levels (48, 78),
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. On the
basis of mutation frequency in those with the lowest 1% of
HDL cholesterol, it was estimated that as many as 10% of
the HDL-deficient individuals in the general population
are heterozygous for ABCA1 mutations (78). This is likely
to be an underestimate, as these studies may have missed
critical intronic or regulatory mutations. Moreover, these
reports did not examine allelic frequencies in subjects
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JOHN F. ORAM AND JAY W. HEINECKE
Several lines of evidence suggest that the liver
ABCA1 pathway in mice is responsible for generating
most of the plasma HDL. Selective hyperexpression of
ABCA1 in the liver using adenovirus transgenes markedly
increases plasma HDL levels (294). Bone marrow transplantation showed that the ABCA1 pathway in peripheral
macrophages in mice makes only a minor contribution to
HDL formation (96). Another study showed that targeted
disruption of liver ABCA1 in chow-fed mice reduced
plasma HDL levels by 80% (153). These observations imply that the major cause of the HDL deficiency in Tangier
patients and ABCA1 knockout mice is an impaired liver
ABCA1 pathway.
It is widely believed that a major function of HDL is
to transport cholesterol from peripheral cells to the liver
for elimination in the bile (90). The studies described
above suggest that ABCA1 plays a major role in this
reverse cholesterol transport pathway. The presumed major precursor for this pathway is lipid-poor apoA-I (69,
210), which is initially synthesized and secreted by the
liver (Fig. 6). Most of this apoA-I may immediately interact with liver ABCA1, but some may circulate to the
periphery where it interacts with ABCA1 on cholesterolloaded cells, particularly macrophages. It is more likely,
however, that most of the lipid-poor apoA-I in peripheral
tissues is generated from the surface of mature HDL
particles that are transported there (Fig. 6, dotted arrow)
(240). The ABCA1-bound apoA-I rapidly acquires free cholesterol and phospholipids, becoming partially lipidated.
Most of these nascent particles then mature into spherical
HDL particles (Fig. 6), which deliver their cholesteryl
esters to the liver for secretion in the bile after binding to
SR-B1, the HDL receptor that selectively transfers cholesteryl esters into hepatocytes. These cholesteryl esters
C. Tissue-Specific Functions
1. Brain
The brain is the most sterol-rich organ in the body,
containing ⬃25% of the total body cholesterol (58). Most
FIG. 6. Model for ABCA1-mediated reverse cholesterol transport. Lipid-free apoA-I is produced by the
liver and acquires free cholesterol (C) and phospholipids (PL) from liver and peripheral cells to form nascent
HDL particles (disks). Nonlipidated apoA-I is cleared
by the kidney. Nascent HDL disks mature into spherical HDL through the action of the cholesterol esterifying enzyme lysolecithin:cholesterol acyltransferase
(LCAT), and the cholesteryl esters (CE) are transferred
to the liver by SR-B1 and to other lipoproteins by CE
transfer protein (CETP). LDL CE is delivered into
hepatocytes after endocytosis of LDL particles by the
LDL receptor (LDLR). The lipoprotein-derived CE is
hydrolyzed in the liver to C, which either is recycled
back into the ABCA1 pathway, is secreted in the bile as
either C or bile acids, or is reassembled into lipoproteins that are secreted into the circulation (not shown).
The remodeling of mature HDL particles by CETP,
hepatic lipase (not shown), and phospholipid transfer
protein (not shown) regenerates lipid-depleted apoA-I
(broken arrow).
Physiol Rev • VOL
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B. Reverse Cholesterol Transport
can also be delivered to the liver after transfer to other
lipoproteins, such as LDL (Fig. 6).
A general function of ABCA1 in reverse cholesterol
transport might be to channel tissue cholesterol into the
hepatic SR-B1 pathway for elimination from the body.
There is evidence that hepatic SR-B1 acts to target HDL
cholesterol for biliary secretion. In polarized cells, SR-B1
selectively sorts HDL protein and cholesterol across the
basolateral and apical membranes, respectively (254).
This polarity in hepatocytes would transport HDL cholesterol into the bile while regenerating apolipoproteins in
the plasma. The major sources of cholesterol entering the
reverse cholesterol transport pathway via peripheral
ABCA1 would likely be cell debris and modified lipoproteins taken up by tissue macrophages. The major sources
of cholesterol secreted by ABCA1 from the liver are probably dietary and lipoprotein cholesterol delivered to the
liver by chylomicron and LDL receptors. This liver-processed sterol may need to be repackaged into HDL particles for efficient biliary secretion.
In support of this concept are studies showing that
HDL, not LDL, is the major source of cholesterol used for
bile acid production (246) and that overexpressing SR-B1 in
mice increases transport of lipoprotein cholesterol into the
bile (254). It has been reported, however, that biliary cholesterol secretion was unimpaired in mice lacking ABCA1
(94), suggesting that either ABCA1 is unnecessary for this
process or that other hepatic mechanisms can compensate
for the absence of ABCA1 and low HDL levels in these
animals. Additional studies are needed to define the role of
hepatic ABCA1 in lipoprotein metabolism.
ABCA1 FUNCTION AND PATHOBIOLOGY
Physiol Rev • VOL
It is believed that accumulation in the brain of
plaques enriched in ␤-amyloid (A␤) peptides causes Alzheimer’s disease. A␤ peptides are small 39- to 42-kDa
secreted cleavage products of a cellular amyloid precursor protein (APP). A␤ production is positively related to
the cholesterol content of neuronal cells, suggesting that
brain cholesterol may be a risk factor for Alzheimer’s
disease (293). In support of this idea are clinical studies
showing that cholesterol-lowering drugs (statins) reduce
the prevalence of this disease (128, 302). Cell culture
studies have generated conflicting results about the influence of ABCA1 on A␤ production, with one study showing
that increased ABCA1 expression increased generation of
A␤ in cultured neuronal cells (81) and two others showing
the opposite effect (142, 259). Although the reason for this
discrepancy is unknown, it may reflect the possibility that
ABCA1 can modulate A␤ production either directly or as
a secondary response to cholesterol depletion. Additional
studies are needed to confirm a role for ABCA1 in A␤
metabolism and Alzheimer’s disease.
2. Intestines
Early studies suggested that ABCA1 in intestinal enterocytes could play a role in promoting resecretion of
sterols back into the intestinal lumen across the apical
membrane and thus reduce absorption of dietary cholesterol. This was largely based on the observation that
LXR/RXR agonists inhibit absorption of dietary cholesterol in mice in association with an induction of intestinal
ABCA1 (141, 231). Since then, two other intestinal LXRinducible ABC transporters (ABCG5 and ABCG8) were
discovered. It now appears that most of the LXR-modulated resecretion of dietary cholesterol in the intestine is
mediated by heterodimers of ABCG5 and ABCG8 (17, 93,
154, 167). Studies of cultured intestinal-derived Caco-2
cells showed that ABCA1 is localized to the basolateral
membrane, as is the case with other polarized cells (68,
118, 200). A lack of ABCA1 in the WHAM chicken did not
impede LXR agonist-induced reduction in dietary cholesterol absorption, but it did suppress cholesterol secretion
from the basolateral side of the intestines (183). Intestinal
cells also synthesize apoA-I and secrete it from the basolateral side (118). It is therefore likely that intestinal
ABCA1 functions to generate HDL particles that transport
dietary cholesterol to the liver.
3. Gallbladder
Bile is the major route of cholesterol secretion from
the body. The concentration of bile during the interdigestive phase in the gallbladder can supersaturate the bile
with cholesterol, exposing the apical side of gallbladder
epithelial cells to high concentrations of cholesterol and
leading to gallstone formation and cholesterolosis. As
with liver and intestinal cells, gallbladder epithelial cells
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of the brain cholesterol is synthesized locally, with only a
small amount transported from the circulation across the
blood-brain barrier (58). Flux of cholesterol out of the
brain occurs largely after conversion to the more polar
24S-hydroxycholesterol, which passively traverses the
blood-brain barrier (20). ABCA1 is highly expressed in
glial and neuronal cells of the central nervous system,
particularly in Purkinje cells and pyramidal cortical neurons (142, 149, 296). There is emerging evidence that
ABCA1 plays an important role in maintaining brain cholesterol homeostasis and protecting against disease.
The major ABCA1-interacting apolipoprotein in the
brain is apoE, which is synthesized locally by glial cells
(169). ABCA1 is highly induced in cultured astrocytes,
neuronal cells, and microglial cells by LXR/RXR ligands,
where it promotes cholesterol and phospholipid efflux to
lipid-free apolipoproteins, including apoE (81, 142, 259).
Interestingly, glial expression of ABCA1 appears to modulate synthesis and secretion of apoE. Glial cells cultured
from mice lacking ABCA1 secreted smaller lipoprotein
particles with a markedly reduced cholesterol and apoE
content compared with cells from ABCA1-expressing animals (109, 280). The cortex and cerebral spinal fluid of
ABCA1-deficient mice have a much lower level of apoE
than those expressing ABCA1 (280). These findings suggest that glial ABCA1 has the dual function of promoting
lipid efflux and generating apolipoprotein lipid acceptors
for lipoprotein particle formation.
ABCA1 is also expressed in cultured brain capillary
endothelial cells (218), where it may play a role in sterol
transport across the blood-brain barrier. These cells synthesize and secrete apoA-I, which can serve as the acceptor for the lipids extruded by ABCA1 (218). With these
cells, however, ABCA1 is localized to the basolateral
membrane and apoA-I is secreted in this direction, consistent with generation of lipoprotein particles in the
brain parenchymal fluid (218). ABCA1 is highly induced in
brain capillary endothelial and glial cells by 24S-hydroxycholesterol through the LXR/RXR system (218). This is
consistent with the possibility of a feedback mechanism,
whereby 24S-hydroxycholesterol-induced ABCA1 generates lipoprotein carriers that transport this oxysterol to
the blood-brain barrier for diffusion into the circulation
(218). Capillary endothelial ABCA1 may also facilitate
transport to the brain of circulating ABCA1 substrates
that are important for neuronal function, such as ␣-tocopherol.
Clinical and cell culture studies have implicated
ABCA1 as being involved in the etiology of late-onset
Alzheimer’s disease, a neurodegenerative disorder affecting memory and cognition in the elderly. Two studies
have reported that genetic variations of ABCA1 modify
risk for Alzheimer’s disease (134, 301), whereas another
case-control study found no influence of ABCA1 polymorphisms on this disease (161).
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JOHN F. ORAM AND JAY W. HEINECKE
express ABCA1 in their basolateral membranes (151).
Interestingly, addition of apoA-I to either the apical or
basolateral sides of these cultured cells stimulates
ABCA1-mediated cholesterol efflux to the basolateral side
(151). This may be because apoA-I induces the synthesis
and basolateral secretion of apoE (152). These cells also
synthesize and secrete apoA-I into the basolateral media
in response to LXR/RXR ligands (152). These observations suggest that ABCA1 in gallbladder epithelial cells
functions to reduce biliary cholesterol content and thus
protects against gallstone formation.
4. Lung
5. Testis
ABCA1 is highly expressed in the testis (296), suggesting that it plays a role in modulating testicular lipid
transport. ABCA1 is enriched in the Sertoli cells of the
seminiferous tubule, which phagocytose residual bodies
and apoptotic sperm cells. ABCA1-deficient mice accumulate lipid droplets in Sertoli cells (250), implying that
ABCA1 promotes removal of excess cellular lipids derived from phagocytosed membranes. Cultured Sertoli
cells lacking ABCA1 fail to transport cholesterol to apolipoproteins (250). The pathological consequences of impaired ABCA1 in these cells are unclear. Although
ABCA1-deficient male mice have lower spermatogenesis
and fertility than wild-type mice (250), this may be due to
the absence of plasma HDL, which is a major supplier of
cholesterol for steroidogenesis by Leydig cells. Moreover,
Physiol Rev • VOL
6. Kidney
Dyslipidemia accelerates the progression of renal
disease, and cholesterol-lowering drugs can retard this
effect (2, 135). Lipid-laden foam cell are frequently
present in glomeruli of subjects with chronic renal disease, suggesting that cholesterol homeostasis in these
cells is disrupted. Several forms of renal injury promote
accumulation of cholesterol within the renal cortex, and
this can induce ABCA1 in proximal tubular cells (129).
Cultured glomerular mesangial cells have been shown to
express LXR-inducible ABCA1, which promotes cholesterol efflux from these cells to apoA-I (303). These results
suggest that ABCA1 may function in the kidney to maintain normal cholesterol homeostasis and protect against
hyperlipidemic renal disease. One study of ABCA1-deficient mice showed the presence of glomerulonephritis,
but this appeared to be due to deposition of immune
complexes in the kidney (43). There have been no published reports of renal disease in human subjects with
dysfunctional ABCA1.
V. ABCA1 AND 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 atheroprotective, it is clear that the relative activity of
ABCA1 plays a major role. Genetic and cell biology studies suggest that low plasma HDL levels in many individuals reflect an impaired ABCA1 pathway, which would
also promote accumulation of cholesterol in tissue macrophages. Accumulation of sterol-laden macrophage
“foam cells” in the artery wall is an early event in formation of atherosclerotic lesions. Thus both the relative
activity of the cellular ABCA1 pathway and the availability of functional apolipoproteins in the artery wall would
be expected to have a major impact on atherogenesis.
These assumptions were borne out by studies of human
subjects with genetic HDL deficiencies and of genetically
modified mice.
A. ABCA1 Activity
Tangier disease homozygotes (or compound heterozygotes) over the age of 30 have a sixfold higher than
normal incidence of CVD (251), 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
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Disruption of the ABCA1 gene in mice leads to an
accumulation of lipids within lung alveolar type II cells,
consistent with ABCA1 playing an important role in lipid
homeostasis in the lung (174). ABCA1 in cultured type II
cells is induced by LXR/RXR ligands and promotes phospholipid efflux from the basolateral side (22, 312). There
is circumstantial evidence that this basolateral phospholipid export may function to modulate surfactant secretion. Surfactant is secreted from the apical side of alveolar type II cells into the alveolus, where it is essential for
normal breathing. The major component of surfactant is
phosphatidylcholine containing saturated fatty acid side
chains. Stimulation of phospholipid synthesis in cultured
murine alveolar cells was reported to induce ABCA1 transcription by an LXR-independent mechanism (312). Because the phospholipids secreted by the ABCA1 pathway
were enriched with unsaturated fatty acids, these results
suggested that ABCA1 might increase the relative saturated phospholipid content of alveolar cells, thus providing the appropriate phospholipids for producing surfactant. Such a mechanism, however, appears to have little
consequences for normal lung physiology in humans, as
there is no evidence that ABCA1-impaired individuals
have breathing difficulties.
there is no evidence for reduced fertility in human male
subjects lacking a functional ABCA1.
ABCA1 FUNCTION AND PATHOBIOLOGY
B. ABCA1-Interacting Apolipoproteins
1. Apolipoprotein supply
The ABCA1 pathway must rely on an adequate supply
of lipid acceptors for optimal activity. Cell culture studies
showed that these are lipid-poor apolipoproteins (210).
The ABCA1-mediated lipid efflux from cultured cells saturates at an apolipoprotein concentration of 10⫺7 M, ⬍1%
of the total plasma concentration of apolipoproteins.
Thus only trace amounts of lipid-poor apolipoproteins
would be required to maximally stimulate this pathway in
vivo, as long as they can be continually regenerated.
Studies of HDL particle composition have shown that
5– 8% of the plasma apoA-I is associated with no or very
little lipid (12). The concentration of lipid-poor apoA-I is
even higher in interstitial fluids where it would have direct
contact with ABCA1. Lipid-poor apoE (111) and apoA-IV
Physiol Rev • VOL
(61) have also been identified in plasma. It would therefore appear that the steady-state supply of lipid-poor apolipoproteins would be in excess of that required to maximally stimulate the cellar ABCA1 pathway in most cases.
Nevertheless, factors that influence the availability and
activity of lipid-poor apolipoproteins in the artery wall
may modulate the atheroprotective effects of ABCA1.
A severe deficiency of apoA-I in both humans and
mice tends to increase CVD, but this is not true in all
cases (278). This inconsistency may reflect the apolipoprotein redundancy in cholesterol mobilization or the
need for other atherogenic factors to be present for apolipoproteins to manifest their protective effects. It is noteworthy that apoA-I null alleles are associated with CVD in
the homozygous state when no evidence of disease exists
in heterozygotes (278), consistent with the concept that
only trace quantities of apolipoproteins are required to
saturate the ABCA1 pathway. Overexpression of apoA-I in
transgenic mice and rabbits increased HDL levels and
reduced CVD (62, 238, 265). These findings conform to the
possibility that the arterial supply of lipid-poor apolipoproteins can be limiting for the ABCA1 pathway. It is
also possible that atheroprotective effects of HDL independent of ABCA1 account for these observations.
Factors that promote regeneration of lipid-poor apolipoproteins from mature HDL particles may also play an
important role in providing lipid acceptors for the ABCA1
pathway. It is possible that distinct subpopulations of
HDL particles are the major sources of apoA-I that dissociates from the particle surface. These could be large
apoA-I-containing particles lacking apoA-II that appear in
the HDL2 subfraction (38). This idea is supported by
studies showing that these particles have a larger fraction
of exchangeable apoA-I (39) and are correlated better
with protection against CVD (38, 79) than are apoA-IIcontaining HDL particles. A reduced availability of lipidpoor apoA-I may contribute to the increased formation of
atherosclerotic lesions in transgenic mice overexpressing
apoA-II (292). Remodeling of HDL particles may also
generate lipid-poor apolipoproteins (Fig. 6). Plasma cholesteryl ester and phospholipid transfer proteins, hepatic
lipase, and scavenger receptor B1 can all produce lipidpoor apoA-I from HDL. In human and mouse models,
variations in expression of these molecules can have either pro- or anti-atherogenic effects (114, 117, 122, 127),
suggesting a complex interaction with other factors. The
relative ability to generate lipid-poor apolipoproteins may
contribute to this complexity.
A poorly understood area of apolipoprotein metabolism relates to factors that modulate apolipoprotein availability in the atherosclerotic lesions. Although HDL apolipoproteins have been shown to accumulate in lesions, it
is unknown what fraction of these is lipid deficient. Apolipoproteins bind to matrix proteins (33), which could
also affect their efficacy in interacting with ABCA1. This
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atheroprotective lipoprotein. Their low levels of LDL may
partially protect these Tangier disease subjects from
atherogenesis. Studies of Tangier disease heterozygotes,
who tend to have more normal levels of LDL, showed a
significant inverse correlation between ABCA1 activity in
their cultured skin fibroblasts and the prevalence and
severity of CVD (47). Dysfunctional ABCA1 mutations
were shown to be associated with greater intima-media
thickness of the carotid arteries (273). In general, premature CVD is associated with ABCA1 mutations that impair
its function (48, 78, 255).
Polymorphisms in ABCA1 are associated with either
increased or decreased CVD (255). Interestingly, many of
these variants show an altered severity of atherosclerosis
without changes in plasma lipid levels.
Mouse model studies have also provided support for
the atheroprotective effects of ABCA1. One report
showed that overexpression of human ABCA1 in transgenic C57Bl/6 mice significantly reduced diet-induced atherosclerosis (132). This was accompanied by a favorable
change in lipoprotein profile. Conflicting data were reported, however, for apoE null mice overexpressing
ABCA1, where one study showed a decrease in atherosclerosis (256) while another showed an actual increase
(132). Studies with ABCA1 null mice have been difficult to
interpret because, as with Tangier disease patients, the
absence of a functional Abca1 gene also lowers plasma
levels of atherogenic lipoproteins (3). This is probably
due to the impact ABCA1 has on liver and intestinal
lipoprotein metabolism. However, reciprocal bone marrow transplantation studies using wild-type and Abca1
null mice have shown that ABCA1 expressed selectively
in macrophages has a significant influence on atherogenesis (3, 274). These studies underscore the importance of
macrophage ABCA1 as a target for therapeutic interventions for treating CVD.
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JOHN F. ORAM AND JAY W. HEINECKE
2. Dysfunctional apolipoproteins
Modification of apolipoprotein structure could impair its ability to interact with ABCA1 and mobilize excess
cholesterol from arterial macrophages. In support of this
possibility is a study showing that most of the apoA-I in
HDL isolated from atherosclerotic lesions migrates as
larger than normal molecular weight species on electrophoretic gels (18), consistent with extensive structural
modifications of HDL apolipoproteins within these lesions. Although apolipoproteins could be modified by
multiple processes, it is likely that oxidation reactions
play a major role.
Many lines of evidence support the hypothesis that
oxidation converts LDL into an atherogenic form in animal models of hypercholesterolemia (104, 105, 299). Oxidized LDL has also been detected in human atherosclerotic lesions (104, 105, 299), raising the possibility that
oxidative modifications of lipoproteins may be clinically
significant. Moreover, chlorinated or nitrated apoA-I has
been found in HDL isolated from human blood and atherosclerotic tissue, indicating that HDL is a target for
oxidation in vivo (18, 221, 310). In vitro, chlorination but
not nitration markedly impairs the ability of apoA-I to
promote cholesterol efflux from artery wall cells by the
ABCA-1 pathway (18, 253, 310).
A) CHLORINATION AND NITRATION OF HDL. One oxidative pathway in the human artery wall involves myeloperoxidase, a
phagocyte heme protein that colocalizes with arterial
macrophages (53). Myeloperoxidase uses H2O2 and chloride to generate hypochlorous acid (HOCl), a powerful
oxidant (113). The importance of this reaction is underscored by the presence of enzymatically active myeloperoxidase in human atherosclerotic lesions (53). In vitro
studies demonstrate that myeloperoxidase or reagent
HOCl converts tyrosine to 3-chlorotyrosine, a stable product (59, 102). Studies of model systems (59, 102) and
myeloperoxidase-deficient mice (85) have demonstrated
that 3-chlorotyrosine is a molecular fingerprint that implicates the myeloperoxidase pathway in oxidative damage.
Physiol Rev • VOL
Levels of 3-chlorotyrosine in HDL isolated from human atherosclerotic lesions were sixfold higher than
those in HDL circulating in human blood (18, 310). They
were eightfold higher in HDL isolated from plasma of
subjects with coronary artery disease than in HDL from
plasma of healthy subjects (18, 310). These findings support the hypothesis that HOCl derived from myeloperoxidase contributes to HDL oxidation in the artery wall.
Another oxidative pathway involves nitric oxide (nitrogen monoxide, NO), which is generated by vascular
wall cells (182). NO reacts rapidly with superoxide to
form peroxynitrite (ONOO⫺), a reactive nitrogen species
(119). ONOO⫺ reacts in vitro with tyrosine residues to
yield nitrotyrosine, a stable product (119). NO can also
⫺
autoxidize to nitrite (NO⫺
2 ), and plasma levels of NO2 rise
markedly during acute and chronic inflammation (182).
Because NO⫺
2 is a substrate for myeloperoxidase and
other peroxidases (63, 64), it might be used to nitrate
tyrosine in vivo. Indeed, myeloperoxidase uses hydrogen
peroxide (H2O2) and NO⫺
2 to generate reactive nitrogen
species that nitrate tyrosine residues in animal models of
inflammation, and this pathway is partially inhibited in
mice deficient in myeloperoxidase (85).
HDL is nitrated on tyrosine residues in vivo (221,
310). Levels of 3-nitrotyrosine were fivefold higher in HDL
isolated from atherosclerotic tissue than in circulating
HDL, and plasma HDL from humans with established
coronary artery disease contained twice as much 3-nitrotyrosine as that from healthy subjects (221, 310). There
was also a strong relationship between levels of 3-nitrotyrosine and 3-chlorotyrosine in plasma HDL, suggesting
that myeloperoxidase is the major pathway for nitrating
HDL that appears in the circulation (221). These observations suggest that elevated levels of 3-chlorotyrosine and
3-nitrotyrosine in circulating HDL might represent a novel
marker for clinically significant atherosclerosis.
A key question is whether chlorination or nitration of
HDL in the artery wall promotes the development of
atherosclerotic plaque. In vitro studies indicate that Tyr192 of apoA-I is the single major target for chlorination by
the myeloperoxidase-H2O2-chloride system or HOCl (18,
253, 311) and for nitration by ONOO⫺ (253, 311). The
ability of apoA-I to promote ABCA1-dependent cholesterol efflux was dramatically impaired when Tyr-192 was
chlorinated (18, 253). In contrast, nitration of Tyr-192 had
little impact on this biological function (253, 310). These
observations indicate that Tyr-192, an aromatic amino
acid, is the major target for oxidation when apoA-I is
exposed to reactive chlorine and nitrogen species and
that chlorination and nitration exert different effects on
the ability of the modified apolipoprotein to promote
ABCA1-dependent cholesterol efflux. It is important to
note that these studies do not prove that chlorination of
Tyr-192 is responsible for impairing apoA-I function be-
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possibility is supported by a study showing that apoA-I
bound to matrix established by cultured macrophages is
more active in removing cellular cholesterol than apoA-I
in solution (32). Bone marrow transplantation studies
have shown that overexpression of apoA-I (171) or apoE
(16) in macrophages reduces CVD in mice. Because apoE
is synthesized and secreted by macrophages, it is likely to
have an autocrine/paracrine effect on the ABCA1 pathway
in lesion cells. ApoE has the additional ability of mobilizing cholesterol from macrophages by ABCA1-independent mechanism during its synthesis and secretion (112).
Macrophages may secrete other molecules that remodel
HDL, such as hepatic lipase (91) or phospholipid transfer
protein (PLTP) (145, 199).
ABCA1 FUNCTION AND PATHOBIOLOGY
Physiol Rev • VOL
rotic mice. It would be of interest to determine whether
similarly modified species of HDL exist in vivo.
Cross-linked heterodimers of apoA-I and apoA-II in
tyrosylated HDL appear to be responsible for the enhanced reverse cholesterol transport (288). ApoA-I crosslinked to apoA-II represented a minor fraction (⬃14%) of
the total apolipoproteins in the tyrosylated HDL used in
the studies of atherosclerotic mice (168). If these heterodimers are responsible for the atheroprotective effects
of tyrosylated HDL, relatively low concentrations of such
cross-linked apolipoproteins (or synthetic peptides)
might be sufficient to strongly affect atherogenesis. These
heterodimers act more like lipid-free apolipoproteins, perhaps because conformational changes in apoA-I expose
more amphipathic ␣-helices to ABCA1. It will be of interest to determine whether tyrosylated HDL interacts with
ABCA1 and to investigate the underlying mechanisms for
enhanced cholesterol transport by this pathway.
C) OTHER OXIDATIVE PATHWAYS. Unmodified HDL protects
LDL from oxidative modification by pathways that require
metal ions (219), and HDL that has been oxidized by
copper loses its ability to remove cholesterol from cultured cells (186, 241). These observations suggest that
metal-catalyzed HDL oxidation is detrimental and should
promote cardiovascular disease. However, the physiological significance of lipoprotein oxidation catalyzed by
metal ions is not yet established (105, 155). Several other
mechanisms, including ability of HDL to inhibit LDL oxidation, reduce lipid hydroperoxides, and transport oxidized lipids to the liver for excretion, may also be cardioprotective (44, 83, 275). Methionine and phenylalanine
residues in apoA-I are oxidized by reactive intermediates,
but it is unclear if this process affects the ability of
apolipoprotein to remove cholesterol from cells (172,
217).
VI. ABCA1 AS A THERAPEUTIC TARGET
The proven atheroprotective activity of ABCA1 has
made this transporter an important new therapeutic target for treating CVD, 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 that an increased liver ABCA1 activity
would elevate plasma HDL levels and thus enhance the
diverse atheroprotective functions of this lipoprotein subclass. The activity of the ABCA1 pathway can be modulated at multiple levels, providing an array of potential
therapeutic targets for enhancing this pathway. While
ABCA1 transcription has received the most attention,
other posttranscriptional processes may prove to be important targets under special circumstances.
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cause other amino acids are also modified when apoA-I is
exposed to oxidizing intermediates (253, 311).
Several lines of evidence suggest that myeloperoxidase-mediated oxidation of apoA-I may be sufficient to
impair ABCA1-dependent cholesterol efflux from macrophage foam cells in the human artery wall (18, 221, 253).
The level of tyrosine chlorination in lesion HDL ranged
from 100 to 300 ␮mol 3-chlorotyrosine/mol Tyr (18), suggesting that ⬃1 in every 800 apoA-I molecules was chlorinated. It is likely, however, that apolipoprotein oxidation is more prevalent in the immediate pericellular environment than in the overall extracellular compartment.
Thus epitopes for 3-nitrotyrosine colocalize with myeloperoxidase and macrophages in human atherosclerotic
tissue (221). Because nitrogen dioxide radical, the source
of 3-nitrotyrosine, is a short-lived species, this finding
implies that proteins in close proximity to macrophages
are prime targets for oxidative damage. Moreover, apoA-I
is poorly nitrated by both myeloperoxidase and ONOO⫺
when it is associated with HDL (253), raising the possibility that lipid-poor apoA-I, the biologically active ligand
for ABCA1, is the major target for nitration in the artery
wall. Thus oxidation of apoA-I appears to be physiologically important, lipid-poor apoA-I may be the primary
target for oxidation, and microenvironments depleted of
antioxidants might enable oxidation to occur. One such
environment surrounds tissue macrophages, which colocalize with myeloperoxidase in the artery wall and generate high local concentrations of oxidants.
B) TYROSYLATION OF HDL. HDL can also be modified by
tyrosylation by exposing particles to tyrosyl radicals generated by a peroxidase. There is evidence that this form of
oxidatively modified lipoprotein might actually retard the
formation of atherosclerotic lesions (168). Hypercholesterolemic mice deficient in apolipoprotein E were protected from atherosclerosis more effectively when they
were injected intraperitoneally with tyrosylated mouse
HDL than when they were treated similarly with native
mouse HDL (168). Because myeloperoxidase produces
tyrosyl radical in vitro, this apparently paradoxical finding
may be relevant to vascular wall biology (106, 107). These
studies are also intriguing because they suggest that not
all forms of oxidized lipoprotein are atherogenic.
The mechanism that allows tyrosylated HDL to protect hyperlipidemic mice from atherosclerosis more effectively than HDL is poorly understood. However, tyrosylated HDL is more effective than native HDL at removing
cholesterol from lipid-laden fibroblasts and macrophages
in vitro by a process that appears to involve interacting
with ABCA1 (76). Consistent with this possibility, production of plasma HDL levels appeared to be higher in the
mice treated with tyrosylated HDL than in those treated
with native HDL (168). These findings suggest that tyrosylated HDL promotes cholesterol efflux from macrophages
and other tissues more effectively than HDL in atheroscle-
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A. Transcriptional Regulation
1. LXR agonists
2. RXR agonists
Agonists for RXR, the heterodimeric partner for LXR,
also stimulate ABCA1 transcription in cultured cells (51,
247). Administration of an LXR agonist to atherosclerotic
mice was shown to reduce atherosclerosis (46). 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
Physiol Rev • VOL
3. PPAR␥ agonists
The nuclear receptor PPAR␥ regulates transcription
of multiple genes involved in cell differentiation and lipid
metabolism. PPAR␥ is also the receptor for thiazolidinediones (TZDs) (157), a class of drugs developed for
treating insulin resistance and type 2 diabetes. Cholesterol loading of macrophages induces PPAR␥ (187), which
has several effects on cholesterol trafficking. PPAR␥ directly stimulates transcription of a scavenger receptor
(CD36) that promotes uptake of oxidized lipoproteins
(269). PPAR␥ also stimulates cholesterol efflux from cells
by increasing ABCA1 expression, an effect that is secondary to inducing LXR␣ (37, 41). In mice, PPAR␥ activators
lessen atherosclerosis (37, 159), suggesting that they have
a favorable effect on macrophage cholesterol balance.
PPAR␥ activators therefore have the potential of both
improving insulin sensitivity and reducing the atherosclerosis that is often associated with diabetes.
B. Posttranscriptional Regulation
Another potential limitation in therapeutic targeting
of ABCA1 transcription is that ABCA1 protein levels and
activity are highly regulated by posttranscriptional processes. The discordance between ABCA1 mRNA and protein levels among mouse tissues underscores the physiological significance of posttranscriptional regulation
(296). For example, heart and kidney were shown to
express relatively high levels of ABCA1 mRNA but were
among tissues with the lowest ABCA1 protein content
(296). It is therefore likely that a variety of diverse cellular
and extracellular factors dramatically influence the cell
content and activity of ABCA1 protein. Cellular factors
would include proteases, signaling enzymes, and partner
proteins, and extracellular factors would include metabolites (e.g., fatty acids and reactive carbonyls), cytokines,
and hormones. These complex processes have received
little attention as therapeutic targets. In many cases, however, the best approach would be treating the underlying
metabolic disorders that generate or modify these factors.
C. Apolipoprotein Supply
Therapeutic strategies to increase ABCA1 activity
would only be effective if there were an adequate supply
of functional apolipoproteins in the artery wall. The striking observation that most of the apoA-I in HDL isolated
from atherosclerosis lesions is structurally modified (18)
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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 (244), which mediates cholesterol efflux to HDL particles (284); apoE (147), which
promotes cholesterol efflux from macrophages by both
ABCA1-independent and -dependent mechanisms (112);
and liver and intestinal ABCG5 and ABCG8 (228), which
promote excretion of liver and dietary cholesterol into the
bile. Thus LXR agonists have the potential for activating
multiple processes that coordinate excretion of excess
cholesterol from the body. Two nonsteroidal synthetic
LXR agonists (TO901317 and GW3965) have been shown
to increase plasma HDL levels and reduce atherosclerosis
in mouse models (130, 180, 268).
A limitation to 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 (229, 245). 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 (212). Moreover,
SREBP-1c induces stearoyl-CoA desaturase, which converts saturated fatty acids to unsaturated fatty acids that
destabilize ABCA1 protein (198). One study showed that
GW3965 can be administered to mice at a concentration
that elevates plasma HDL levels without causing hypertriglyceridemia (180), although this agonist activates
SREBP-1c at high concentrations in vitro (224). A synthetic oxysterol ligand for the LXR receptor was shown to
stimulate ABCA1 synthesis with only a limited ability to
increase hepatic SREBP-1c (224), indicating that divergent gene regulation by LXR is possible. A major challenge is to produce potent synthetic LXR agonists that
selectively induce ABCA1 and other cholesterol transporters.
expression. It was reported, however, that retinoic acid
receptor activators can induce ABCA1 without affecting
other LXR-targeted genes (50), raising the possibility of
selective drug therapy through the RXR system.
ABCA1 FUNCTION AND PATHOBIOLOGY
Physiol Rev • VOL
antioxidants, such as ␤-carotene and vitamins C and E,
could have therapeutic benefits for treating CVD. Large
randomized trials, however, have failed to show a consistent ability of antioxidant vitamins, either alone or in
combination, to reduce clinical coronary end points (92,
103). Design of effective atheroprotective antioxidants
will require more knowledge about the specific oxidation
pathways involved in damaging apolipoproteins and their
functional consequences.
Another strategy for protecting apolipoproteins from
damage would be to administer apolipoproteins or peptides that are resistant to oxidation. Amino acid residues
in apoA-I that are targeted for oxidative modification
could be mutagenized to residues resistant to these modifications. It should also be possible to engineer small
apolipoprotein mimetic peptides that are resistant to oxidation.
VII. CONCLUSIONS
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. ABCA1 may also play a
role in transporting a variety of other compounds, including vitamins and peptides. There is also evidence that
ABCA1 is involved in processes other than modulating
lipid homeostasis, such as promoting macrophage engulfment of apoptotic cells and generating microparticles that
bleb from cell membranes. ABCA1 expression and activity are highly regulated by transcriptional and posttranscriptional mechanisms. Although transcriptional induction by sterols conforms to its role as a cholesterol exporter, the biological relevance of other regulatory
processes is still unclear.
The HDL-elevating and atheroprotective functions of
ABCA1 have made this transporter an important new
therapeutic target for preventing and even reversing atherosclerotic CVD. First-generation protocols have focused on development of LXR agonists that stimulate
transcription of ABCA1 and other genes involved in cholesterol transport. The potential benefits of these agents
have been overshadowed by their broad specificity for
lipogenic genes. Several studies, however, have offered
proof-in-principle that drugs selective for cholesterol
transport genes can be developed in the near future.
There are several lines of evidence that challenge the
therapeutic benefits of targeting ABCA1 transcription.
First, ABCA1 transcription in cells overloaded with cholesterol may already be maximally induced and thus resistant to further induction by agonists. Second, results
showing a strong discordance between ABCA1 mRNA
and protein levels in mouse tissues implicate posttran-
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is consistent with the possibility that the lesion environment damages apolipoproteins, impairing their ability to
remove cellular cholesterol from macrophages by the
ABCA1 pathway. In this case, effective CVD therapy
would need to be directed at increasing the arterial supply
of functional ABCA1 ligands or at blocking apolipoprotein-damaging reactions.
There are multiple biochemical processes that control the production, degradation, and regeneration of lipid-poor apolipoproteins (see Fig. 6), and each one is a
potential therapeutic target for elevating ABCA1 ligands.
It has also been demonstrated that infusion of HDL apolipoproteins into animals and humans can retard or reverse atherosclerosis. Infusion of apoA-I into cholesterolfed rabbits was shown to significantly retard atherosclerosis (181). As discussed above, infusion of tyrosylated
HDL into atherosclerosis-susceptible mice reduced
atherogenesis to a greater extent than infusion of normal
HDL (168). Phospholipid vesicles containing a naturaloccurring mutant form of apoA-I (R173C), called apoA-I
(Milano), reduced atherosclerosis when infused into animal models (40, 252) or human subjects (196). ApoA-I
(Milano) was identified in family members from rural Italy
who had very low levels of HDL but unusual longevity,
implying that their HDL is cardioprotective. A clinical trial
showed that weekly intravenous injections of apoA-I (Milano)-phospholipid vesicles into human subjects with established CVD reduced atheroma volume by 4.2% after
only 5 wk (196). It is unknown, however, if injections of
native apoA-I would have had similar effects. The atheroprotective mechanisms of infused apolipoproteins have
not been established, but it is possible that ABCA1 interactions play a role.
One promising therapeutic approach involves administrating amphipathic ␣-helical peptide mimetics of apolipoproteins. A mimetic peptide containing 18 D-amino acids (D-4F) is absorbed orally into the bloodstream of mice
where it has a low rate of turnover (190). Administration
of this peptide in the drinking water was shown to markedly reduce atherosclerosis in mouse models (190). These
effects were associated with an increase in the anti-inflammatory properties of HDL particles and an enhanced
cholesterol efflux from macrophages (191), 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.
Prevention of oxidative damage to apolipoproteins in
the artery wall could also be an important therapeutic
approach for enhancing the ABCA1 pathway. Lipid-soluble antioxidants have been shown to inhibit atherogenesis
in hypercholesterolemic animal models (56), which may
stem from their ability to inhibit oxidation of both LDL
and HDL. These studies raised the possibility that dietary
1363
1364
JOHN F. ORAM AND JAY W. HEINECKE
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
ACKNOWLEDGMENTS
Address for reprint requests and other correspondence:
J. F. Oram, Dept. of Medicine, Box 356426, Univ. of Washington,
Seattle, WA 98195-6426 (E-mail: [email protected]).
17.
GRANTS
The authors’ work described in this review was supported
by National Institutes of Health Grants HL-18645, HL-75340,
HL-55362, and DK-02456.
18.
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