© 2000 American Heart Association, Inc.
Editorials |
A, B, C...
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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.
Key Words: ABC1 • LXR • HDL • foam cell • atherosclerosis
Tangier 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 4 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 4 5 Importantly, heterozygous mutations can also cause the more common forms of familial hypoalphalipoproteinemia.4
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 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 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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