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ISSN 1672-9145

Acta Biochimica et Biophysica Sinica 2006, 38(3): 151156

CN 31-1940/Q

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Human Acyl-CoA:cholesterol Acyltransferase (ACAT) and its Potential as a


Target for Pharmaceutical Intervention against Atherosclerosis
1

Catherine CHANG *, Ruhong DONG , Akira MIYAZAKI , Naomi SAKASHITA , Yi ZHANG , Jay LIU ,
1
4
1
Michael GUO , Bo-Liang LI , and Ta-Yuan CHANG
1

Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755 USA;
2
Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan;
Second Department of Pathology, Kumamoto University School of Medicine, Kumamoto, Japan;
4
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences, Shanghai 200031, China
3

Key words

acyl-CoA:cholesterol acyltransferase; cholesterol; cholesteryl ester; atherosclerosis

Acyl-CoA:cholesterol acyltransferase 1
Two acyl-CoA:cholesterol acyltransferase (ACAT) genes
have been identified in mammals: ACAT1 and ACAT2. The
ACAT1 gene was first identified in 1993 by virtue of its
ability to functionally complement the ACAT deficiency of
a Chinese hamster ovary (CHO) cell mutant [9]. Using
ACAT1-specific antibodies, Miyazaki et al. [10] examined
human atherosclerotic lesions using immunohistochemical
staining. These results showed that in early lesions of the
human aorta, mononuclear cells expressed only limited
ACAT1. In contrast, the same ACAT1 antibodies stained
much more intensely in fatty streak lesions, particularly in
areas that contained macrophages with foamy transformation (Fig. 1). This demonstrates that ACAT1 is a marker
for the early development of human atherosclerosis. To
determine the cell types in this region, in the same study
Received: January 9, 2006
Accepted: February 7, 2006
*Corresponding author: E-mail, Catherine.Chang@dartmouth.edu

Miyazaki et al. used Oil-Red-O to identify the lipid-rich


region, followed by double immunostaining (Fig. 2). The
results demonstrated that monocytes/macrophages were
the major cellular component of the ACAT1-expressing
cells in atherosclerotic lesions [10]. These findings have
potential clinical significance because it is known that plaque
ruptures associated with acute myocardial infarction generally
occur in the plaques shoulder regions that are filled with
lipid-rich, foamy macrophages [11,12].
Human ACAT1 (hACAT1) expressed in CHO cells or in
insect H5 cells has been purified to homogeneity with
retention of catalytic activity [13]. hACAT1 is a homotetrameric integral membrane protein [14] and mainly
resides in the endoplasmic reticulum [15,16]. Unlike many
enzymes involved in cholesterol metabolism, ACAT1 is not
regulated by cholesterol at the transcriptional level. The
main mode of sterol-specific regulation of ACAT1 is at
the post-translational level, involving allosteric activation
by its own substrate, cholesterol [13]. Kinetic analysis
DOI: 10.1111/j.1745-7270.2006.00154.x

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Abstract
Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes the formation of cholesteryl esters
from cholesterol and long-chain fatty-acyl-coenzyme A. At the single-cell level, ACAT serves as a regulator
of intracellular cholesterol homeostasis. In addition, ACAT supplies cholesteryl esters for lipoprotein
assembly in the liver and small intestine. Under pathological conditions, the accumulation of cholesteryl
esters produced by ACAT in macrophages contributes to foam cell formation, a hallmark of the early
stage of atherosclerosis. Several reviews addressing various aspects of ACAT and ACAT inhibitors are
available [18]. This review briefly outlines the current knowledge on the biochemical properties of human
ACATs, and then focuses on discussing the merit of ACAT as a drug target for pharmaceutical interventions
against atherosclerosis.

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(A) Diffuse intimal thickening. (B) Fatty streak. Clear immunoreactivity for antiACAT1 antibodies (DM10) is recognized in both endothelial layer and a small
amount of infiltrated mononuclear cells in the early lesion of atherosclerosis (A). In
the fatty streak lesions, prominent ACAT1 expression is found in the infiltrated
macrophages with or without foam cell transformation (B). Bar=100 m. From
Miyazaki et al. [10].

comparing various oxysterols to cholesterol as a substrate


and as an activator revealed that ACAT1 might contain two
types of sterol binding sites. The first site is the activator
site, which strongly prefers cholesterol to oxysterols or
any other sterol analogs examined. Activation of ACAT1
by cholesterol causes the second site, the substrate-binding
site, to accommodate a variety of sterols, including
cholesterol, oxysterols, plant sterols, and various other
sterols as the enzymatic substrate and facilitates enzyme
catalysis [17]. The mode of activation was further analyzed
by using a specific cholesterol analog called enantiomeric
cholesterol. Enantiomeric cholesterol is the mirror image
of cholesterol. In membranes, it possesses identical
biophysical properties as cholesterol [18]. The results
showed that activation of ACAT1 occurs with cholesterol,
but not with enantiomeric cholesterol [19]. These results
indicate that the activation mechanism mainly involves
stereo-specific interaction, rather than biophysical effects
of cholesterol on phospholipid membranes.
In hepatocytes, ACAT1 can provide cholesteryl esters
(CEs) for very low-density lipoprotein (VLDL) assembly
[20,21]. In macrophages and other cell types, ACAT1 is
involved in forming CEs as lipid droplets [10,16]. The VLDL
assembly process occurs within the lumens of the intracellular membrane compartment(s), while the lipid droplets

Fig. 2
Histochemical demonstration of lipid deposition and
immunohistochemical localization of ACAT1 within monocytesmacrophages in the human atherosclerotic plaque
(A) Oil-Red-O staining (red). Numerous lipid droplets have accumulated in the
atheromatous plaque shoulder (the central portion). The necrotic center (the cellular area on the right side) contains a limited number of lipid droplets. (B) Double
immunohistochemical staining with anti-ACAT1 antibodies DM10 (brown) and
anti-monocyte-macrophage antibodies EBM11 (blue). DM10 and EBM11 doublepositive cells are demonstrated in the atheromatous plaque shoulder. (C) Highmagnification view of panel (B). The scale bars in (A) and (B) indicate 200 m; in
(C) the bar indicates 100 m. From Miyazaki et al. [10].

are formed in the cell cytoplasm. For ACAT1 to fulfill its


dual roles, it has been hypothesized that the active site of
ACAT1 may be located within the plane(s) of the ER
membrane, such that the enzyme biosynthesizes CEs within
the ER membrane [22]. This arrangement would enable the
CE formed to leave the cytoplasmic leaflet of the membrane
to form lipid droplets or to be recruited to the lumen of the
membrane by the protein microsomal lipid transfer protein
(MTP) for the VLDL assembly process. The recent

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Fig. 1
Immunohistochemical detection of ACAT1 in the
human atherosclerotic intima

Mar., 2006

Catherine CHANG et al.: Human Acyl-CoA:cholesterol Acyltransferase (ACAT) and its Potential as a Target

153

evidence reported by Guo et al. [23] demonstrating that


ACAT1 contains 9 transmembrane domains, with the active
site H460 located within transmembrane domain #7,
provided the experimental support for this hypothesis.

ACAT2

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In 1998 the second ACAT gene, designated as ACAT2,


was simultaneously identified in monkeys, mice and
humans [2426]. ACAT2 shares high homology with
ACAT1 near the C-terminus, but not near the N-terminus.
The kinetic properties of ACAT2 are quite similar to those
of ACAT1 [19,21]. However, membrane topology study
has shown that human ACAT2 contains only two detectable
transmembrane domains [27]. Its active site, H432 (the
equivalent of H460 in hACAT1) may also be located within
the plane of the membrane lipid bilayer [27]. Tissue
distribution studies have shown that the expression of
ACAT1 mRNA and protein is nearly ubiquitous in the human
body, whereas the expression of ACAT2 is more restricted.
Both ACAT1 and ACAT2 are present in human fetal and
adult jejunum samples, with ACAT2 preferentially located
at the apical half of the villi, whereas ACAT1 is uniformly
distributed along the villus-crypt axis. The real-time PCR
analyses showed that in normal human intestines, Acat2
mRNAs are approximate three-fold in abundance over
those of Acat1 [28]. Further experiments using
histochemical staining, Western blot analysis, and
immunodepletion have shown that in the normal (i.e.,
nondiseased) adult livers, ACAT1 is the major isoenzyme
and is present in both Kupffer cells and hepatocytes [16,21].
In contrast, the ACAT2 signal is barely detectable in either
human hepatocytes or Kupffer cells. A representative result
comparing the expression levels of ACAT1 and ACAT2 in
human liver sample is shown in Fig. 3. These findings are
supported by the real-time PCR analyses, which showed
that in normal human livers the abundance of Acat1
mRNAs predominates over those of Acat2 by approximately nine-fold [28]. However, a different study showed
that the immunoreactive ACAT2 protein signals are amply
present in human hepatocytes isolated from patients
affected with gallstone disease [29]. Thus, the relative
functional importance of ACAT1 and ACAT2 in human
hepatocytes is not clear at present and requires further
investigation.
More recently, using Western blot, histochemical staining,
and RT-PCR analyses, Sakashita et al. demonstrated that
immature macrophages expressed only ACAT1, but fully
differentiated macrophages expressed both ACAT1 and

Fig. 3
Immunohistochemical staining using specific antibodies against ACAT1 (A), ACAT2 (B), and Kupffer cells (C) in
the same human liver sample
ACAT1 signal (brown) is most prominent in Kupffer cells, followed by hepatocytes.
In contrast, no positive signal is detected in Kupffer cells or in hepatocytes by
using ACAT2 antibodies. Anti-CD68 stain Kupffer cells (brown) can be visualized
in (C). Nuclei stains are shown in green color. From Sakashita (unpublished data).
Bar=100 m.

ACAT2. In addition, ACAT2 is also present in macrophages


of human atherosclerotic lesions [30]. Thus, the tissue

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Acta Biochim Biophys Sin

distribution of human ACAT2 is not as restricted as previously


believed. The limited data available suggest that within the
same cell, ACAT1 expression may be constitutive, while
that of ACAT2 may be inducible.

ACAT inhibitors

[37] and Yagyu et al. [38] crossed ACAT1-deficient


(ACAT1-/-) mice with either apoE- (apoE-/-) or LDL
receptor-deficient (LDLR-/-) mice. These double-knockout
mice developed extensive deposition of free cholesterol in
the skin and brain [37,38]. Fazio et al. used LDL receptordeficient (LDLR-/-) mice reconstituted with ACAT1-/donor bone marrow, which led to the accumulation of free
cholesterol in the mouse artery wall. As a result, these mice
developed larger atherosclerotic lesions than the control
LDLR-/- mice did [39]. From these results, the authors
suggest that inhibition of ACAT1 may promote lesion
development. However, data from mouse knockout models
may not always be relevant to human pharmaceutical
applications. ACAT1-/- mice show a complete absence of
ACAT1 enzyme, a condition that does not occur with
pharmaceutical interventions on ACAT1 in animals or in
human patients. Therefore, the mouse knockout model is
probably most appropriate for demonstrating the effects
of drug overdoses that may cause detrimental effects in
animals or in humans. To investigate the efficacy of partial
ACAT inhibition, Kusunoki et al. [40] treated apoEknockout mice with a low-dose ACAT inhibitor, which
resulted in diminution of arterial lesion size, an increase of
smooth muscle cells, and a more stable appearance of the
shoulder area [40]. These results suggest that partial
inhibition of ACAT could be an effective therapeutic
treatment for atherosclerosis.

Fig. 4
Photomicrographs showing the size of rabbit iliac-femoral lesions and the distribution and abundance of esterase-positive
monocyte-macrophages within the lesion in control (A) and the ACAT inhibitor CI976-treated (B) animals
Note the reduced lesion size and relative paucity of monocyte-macrophages within the CI-976-treated animals. Alpha-Naphthol esterase stain. Magnification, 25 . From
Bocan et al. [36].

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Starting in the 1980s, small molecules that serve as


specific ACAT inhibitors have become available. In cell
culture, ACAT inhibitors have been shown to reduce cellular
cholesteryl ester content [31,32]. In macrophages and
cholesteryl ester-rich hepatoma cell lines, the cholesteryl
ester-reducing effect of ACAT inhibitors is generally attributed not only to direct inhibition of ACAT, but also to their
ability to increase cholesterol efflux to various cholesterol
acceptors present in the growth medium [3335]. In 1991,
Bocan et al. [36] showed that feeding low-dose ACAT
inhibitor CI-976 to cholesterol-fed rabbits reduced the size
of foam cell lesions without affecting plasma cholesterol
levels (Fig. 4). This study suggests that at low dose, the
primary action of the ACAT inhibitor occurs at the foam cell,
not at the liver. It also provides the first in vivo evidence that
ACAT inhibitors may possess an anti-atherosclerosis effect
without significantly affecting total plasma cholesterol level.
However, other laboratories using ACAT1 gene knockout
mouse models obtained disappointing results. Accad et al.

Vol. 38, No. 3

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Catherine CHANG et al.: Human Acyl-CoA:cholesterol Acyltransferase (ACAT) and its Potential as a Target

tion of drugs concurrently administered. If combination


therapy is to be tested, care must be exercised to avoid
drug-drug interactions.

Acknowledgements
We thank Ellen CHANG and Kathy SAVAGE for critical
reading of this article.

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One early concern in developing ACAT inhibitors was


adrenal toxicity. The cause for adrenal toxicity is probably
caused by a certain chemical structure, which is unrelated
to the ability of the compound to inhibit ACAT. Recent
advances in pharmaceutical research, this concern seems to
have been eliminated [41]. Another major concern for using
the ACAT inhibitor is cellular toxicity induced by free
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atherosclerotic lesions under conditions where cellular
sterol efflux becomes severely hampered.
Coronary heart disease (CHD) is one of the leading
causes of morbidity and mortality in industrialized countries.
Hypercholesterolemia is one of the major risk factors for
progression of atherosclerosis. The development of HMGCoA reductase inhibitors, i.e., statins, has significantly
reduced the mortality of CHD patients by 20%35%,
saving the lives of millions of people each year [44]. On
the other hand, even with the aid of statins, CHD-related
mortality remains high. There is still a need to identify
other compounds that would complement the action of
statins and might further reduce CHD incidence and
mortality. One of these potential novel agents is the ACAT
inhibitor. Different from the effect of statins, which work
mainly by reducing plasma cholesterol, the ACAT inhibitors
may work by directly reducing the size of the lipid-rich
core in the atherosclerotic plaques, thus stabilizing the
lesion against plaque rupture.
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may be inducible in different tissues under various pathological conditions [29,30]. Therefore, before the roles of
ACAT1 and ACAT2 in each tissue/cell type are clarified,
developing a general ACAT inhibitor against both ACAT1
and ACAT2 may be advisable. There are currently several
ACAT inhibitors being tested in clinical trials. We look
forward to learning the results from these ongoing trials,
which will help determine whether ACAT inhibition in
patients with CHD provides promise in the treatment of
atherosclerosis. In this regard, it is worthwhile to cite the
recent work of Sahi et al. [45], who showed that the ACAT
inhibitor Avasimibe induces the cytochrome CYP3A4 in
human hepatocytes, thus promoting the hepatic inactiva-

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