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J. Biol. Chem., Vol. 277, Issue 35, 31893-31899, August 30, 2002
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From the Cholesterol ester (CE)-laden foam cells are a
hallmark of atherosclerosis. To determine whether stimulation of the
hydrolysis of cytosolic CE can be used as a novel therapeutic modality
of atherosclerosis, we overexpressed hormone-sensitive lipase (HSL) in
THP-1 macrophage-like cells by adenovirus-mediated gene delivery, and
we examined its effects on the cellular cholesterol trafficking. We
show here that the overexpression of HSL robustly increased neutral CE
hydrolase activity and completely eliminated CE in the cells that had
been preloaded with CE by incubation with acetylated low density
lipoprotein. In these cells, cholesterol efflux was stimulated in the
absence or presence of high density lipoproteins, which might be at
least partially explained by the increase in the expression of ABCA1.
Importantly, these effects were achieved without the addition of
acyl-CoA:cholesterol acyltransferase inhibitor, cAMP, or even high
density lipoproteins. Furthermore, the uptake and degradation of
acetylated low density lipoprotein was significantly reduced probably
by decreased expression of scavenger receptor A and CD36. Notably, the
cells with stimulated CE hydrolysis did not exhibit either buildup of
free cholesterol or cytotoxicity. In conclusion, increased hydrolysis
of CE by the overexpression of HSL leads to complete elimination of CE
from THP-1 foam cells not only by increasing efflux but also by
decreasing influx of cholesterol.
Elimination of Cholesterol Ester from Macrophage Foam
Cells by Adenovirus-mediated Gene Transfer of Hormone-sensitive
Lipase*
,,,,,,,,,,,,,,
**
Department of Metabolic Diseases and the
¶ Department of Cardiovascular Medicine, Faculty of Medicine,
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, § Metabolism, Endocrinology, and Atherosclerosis, Institute
of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba,
Ibaraki 305-8575, and Division of Endocrinology and Metabolism,
the Department of Medicine, Jichi Medical School, 3311-1 Yakushiji,
Minamikawachi-machi, Kawachi-gun, Tochigi 329-0498, Japan
*
This work was supported by a grant-in-aid for Scientific
Research from the Ministry of Education, Science and Culture, the Promotion of Fundamental Studies in Health Science from the
Organization for Pharmaceutical Safety and Research, and Health
Sciences Research grants (Research on Human Genome and Gene Therapy)
from the Ministry of Health and Welfare.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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