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Kultur Dokumente
CN 31-1940/Q
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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 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
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.
152
(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].
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].
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
ACAT2
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.
http://www.abbs.info; www.blackwellpublishing.com/abbs
154
ACAT inhibitors
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].
Mar., 2006
Catherine CHANG et al.: Human Acyl-CoA:cholesterol Acyltransferase (ACAT) and its Potential as a Target
Acknowledgements
We thank Ellen CHANG and Kathy SAVAGE for critical
reading of this article.
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Ming-Hua XU
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