Elimination of cholesterol ester from macrophage foam cells by adenovirus-mediated gene transfer of hormone-sensitive lipase.
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.
Okazaki
Hiroaki
H
Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Osuga
Jun-ichi
J
Tsukamoto
Kazuhisa
K
Isoo
Naoyuki
N
Kitamine
Tetsuya
T
Tamura
Yoshiaki
Y
Tomita
Sachiko
S
Sekiya
Motohiro
M
Yahagi
Naoya
N
Iizuka
Yoko
Y
Ohashi
Ken
K
Harada
Kenji
K
Gotoda
Takanari
T
Shimano
Hitoshi
H
Kimura
Satoshi
S
Nagai
Ryozo
R
Yamada
Nobuhiro
N
Ishibashi
Shun
S
D000107:Acetylation; D000256:Adenoviridae; D000818:Animals; D001161:Arteriosclerosis / Q000503:physiopathology; D002460:Cell Line; D002470:Cell Survival; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism*; D003470:Culture Media; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism*; D018014:Gene Transfer Techniques; D007700:Kinetics; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D008861:Microsomes / Q000201:enzymology; D019301:Oleic Acid / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism*
D002788:Cholesterol Esters; D003470:Culture Media; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D011994:Recombinant Proteins; D019301:Oleic Acid; D002784:Cholesterol; D002787:Sterol Esterase; D008049:Lipase