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Editorial
A, B, C. . .␥!
Alan R. Tall, Christian W. Schindler
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main HDL apolipoprotein.10 ApoA-I appears to interact with
ABC1 on cell surfaces absorbing lipid and giving rise to small
HDL particles. Subsequently, in the circulation phospholipid
transfer protein moves phospholipids from triglyceride-rich lipoproteins onto the nascent HDL, and lecithin:cholesterol acyltransferase generates cholesterol ester giving rise to the mature
HDL particle.11 Upregulation of ABC1 expression is likely to
enhance cholesterol efflux from macrophage foam cells and may
also result in increased HDL levels, especially in settings in
which there is increased formation of free apoA-I or small HDL
in the bloodstream. This might include the common atherogenic
hypertriglyceridemia-low HDL human condition, in which cholesterol ester transfer protein and hepatic lipase act together to
produce small HDL or free apoA-I.12
The ABC1 molecule is likely to be highly regulated by a
variety of different mechanisms.13 In certain cells ABC1 is
upregulated by cAMP treatment,7 which likely explains the
earlier observations that cAMP treatment of RAW macrophages
increases the efflux of cholesterol to apolipoproteins and HDL.14
ABC1 is also markedly upregulated by cholesterol loading of
cells, an effect opposed by HDL-mediated cholesterol efflux.13
This indicates a positive sterol feedback control loop regulating
ABC1 gene expression. Recently other molecules involved in
the reverse cholesterol transport pathway (CETP, cyp7a) have
been shown to be upregulated by the nuclear hormone transcription factors, LXRs, which heterodimerize with RXR and are
activated by hydroxylated sterols.15,16 Thus, LXRs may help to
coordinate multiple steps in the reverse cholesterol transport
pathway, including the regulation of ABC1 expression by sterols.
ABC1 may also be upregulated on a posttranscriptional level,
because it is phosphorylated by a protein kinase A mechanism.17
In the article in this issue by Panousis and Zuckerman,18
ABC1 mRNA is shown to be markedly downregulated by
interferon ␥ (IFN-␥) treatment of thioglycollate-elicited mouse
peritoneal macrophages. This effect was seen in cells under basal
conditions and also after upregulation of ABC1 expression by
cholesterol loading, suggesting that IFN-␥ and sterols mediate
regulation by different mechanisms. This decrease in ABC1
mRNA was not mediated by other cytokines, and IFN-␥ treatment did not influence the expression of another ABC transporter, TAP, indicating specificity of the effect. Although the
authors did not measure ABC1 protein expression, they were
able to demonstrate that IFN-␥ treatment produced a profound
defect in the efflux of cholesterol to apoA-I and a less marked
decrease in efflux of cholesterol to HDL. Because these changes
are characteristic of ABC-1-mediated cholesterol efflux, it is
likely that IFN-␥ treatment led to a decrease in functional
ABC-1 protein being expressed in macrophages.
This study was conducted as a follow-up to an earlier paper in
which the authors first showed that IFN-␥ treatment produced a
defect in cholesterol efflux to HDL. It was found that IFN-␥
caused a moderate increase in ACAT-1 mRNA expression and
angier disease is a rare recessive genetic disorder, characterized by extremely low HDL levels, accumulation of
cholesterol esters in macrophages, and premature coronary heart disease.1 The observation that fibroblasts from Tangier disease patients have a marked defect in efflux of cholesterol
and phospholipids to apoA-I provided a key insight into the
underlying defect.2 Recently, 3 different groups made the exciting discovery that Tangier disease is caused by mutations in an
adenosine triphosphate (ATP) binding cassette transporter,
ABC1.3–5 Thus, it is likely that ABC1 mediates or regulates the
efflux of cellular cholesterol and phospholipids to apoA-I.
Although ABC1 is widely expressed, the brunt of the defect is
seen in macrophages, indicating their absolute dependence on an
active cholesterol efflux pathway. The nature of the ABC1
molecule and the consequences of its mutation provide important evidence that reverse cholesterol transport underlies the
atheroprotective effect of HDL. Already a multiplicity of ABC1
mutations have been described.3–5 Importantly, heterozygous
mutations can also cause the more common forms of familial
hypoalphalipoproteinemia.4
See p 1565
The ABC1 molecule contains 2 clusters of 6 transmembrane domains and internal loops with nucleotide binding
motifs. Similar ABC transporters have been described to act
as phospholipid flippases, ie, they utilize ATP to transfer
phospholipids from the inner to the outer leaflet of cellular
membranes.6 Although ABC1 is expressed in the plasma
membrane,7 it could also be active at intracellular sites such
as the golgi. Based on a detailed electron microscopic
analysis of a related ABC transporter, the multidrug resistance P-glycoprotein, it is likely that the 2 clusters of
transmembrane domains surround a large aqueous chamber
that opens to the outside of the cell through a pore.8 The
limiting diameter of this pore may explain why ABC1
preferentially transfers lipids to apoA-I and possibly small
HDL. The central chamber also interfaces with the hydrophobic interior of the membrane but not with the cytoplasmic
face of the inner membrane leaflet, suggesting a route for
phospholipid flipping. In contrast to the active efflux mediated by ABC1, the passive exchange of free cholesterol
between HDL and cellular membranes may be facilitated by
scavenger receptor BI (SRBI).9
The low HDL in Tangier disease is due to hypercatabolism of
apoA-I, which is produced in the liver and intestine and is the
From the Departments of Medicine (A.R.T., C.W.S.) and Microbiology (C.W.S.), Columbia University, New York.
Correspondence to Alan R. Tall, Columbia University, College of
Physicians and Surgeons, 630 West 168th Street, New York, NY 10032.
(Arterioscler Thromb Vasc Biol. 2000;20:1423-1424.)
© 2000 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
1423
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Arterioscler Thromb Vasc Biol.
June 2000
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that ACAT activity was increased about two-fold in a whole cell
ACAT assay. It is likely that the increased activity reflected both
an increase in ACAT mRNA as well as an increase in intracellular pools of cholesterol that act as ACAT substrates, secondary
to the decrease in active ABC1.
IFN-␥ has been observed to regulate a number of other genes
involved in lipid metabolism, providing some intriguing parallels to its regulation of ABC1. These genes include scavenger
receptor A and CD36 in macrophages, collagen production in
smooth muscle cells, and apoA-IV expression in hepatocytes. In
each case, IFN-␥ has been shown to downregulate the expression of these genes.14,20 This contrasts with the classical ability
of IFN-␥ to upregulate the expression of a large number of
proinflammatory genes (eg, iNOS, TAP1, and MCH class II)
through the transcription factor Stat1.21 These proinflammatory
activities may contribute to atherosclerosis as well. A number of
potential mechanisms have emerged on how IFN-␥ signaling
may antagonize the expression of some genes. This includes
competition for rate limiting components of the basal transcription machinery, upregulation of inhibitory molecules, and of
note a direct antagonism of interleukin 4 (IL-4) stimulated
signaling.21,22 This later observation may provide some insight
into the regulation of ABC1. IL-4 has recently been shown to
stimulate expression of CD36, a receptor for the uptake of
modified apoB containing lipoproteins, through the coordinate
induction of 12/15-lipoxygenase and peroxisome proliferated
activated receptor–␥, a nuclear hormone receptor.23 IFN-␥ antagonizes IL-4 dependent expression of 15-lipoxygenase (the
human equivalent of 12/15-lipoxygenase), so perhaps the ability
of IFN-␥ to antagonize the cholesterol induced expression of
ABC1 may be achieved through the downregulation of 12/15
lipoxygenase.
Although IFN-␥ has a number of complex, potentially opposing effects, which may influence atherogenesis, the decrease in
atherosclerosis in IFN-␥ receptor/apoE double KO mice indicates that it has a predominant proatherogenic role in vivo.24 The
downregulation of ABC1 by IFN-␥ may now be added to the list
of its proatherogenic effects. These are important observations
that may serve to link an arterial wall inflammatory response
involving interferon-producing T cells with a defect in reverse
cholesterol transport. ABC1 emerges as an attractive target for
pharmacological upregulation because this should enhance cholesterol removal from macrophage foam cells, as well as increase HDL levels. The marked regulation of ABC1 by cytokines and cellular cholesterol stores suggests that it may be
possible to achieve this through a transcriptional mechanism.
References
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KEY WORDS: ABC1
䡲
LXR
䡲 HDL 䡲
foam cell
䡲
atherosclerosis
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A, B, C…γ!
Alan R. Tall and Christian W. Schindler
Arterioscler Thromb Vasc Biol. 2000;20:1423-1424
doi: 10.1161/01.ATV.20.6.1423
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