Identification of neutral cholesterol ester hydrolase, a key enzyme removing cholesterol from macrophages.
Unstable lipid-rich plaques in atherosclerosis are characterized by the accumulation of macrophage foam cells loaded with cholesterol ester (CE). Although hormone-sensitive lipase and cholesteryl ester hydrolase (CEH) have been proposed to mediate the hydrolysis of CE in macrophages, circumstantial evidence suggests the presence of other enzymes with neutral cholesterol ester hydrolase (nCEH) activity. Here we show that the murine orthologue of KIAA1363, designated as neutral cholesterol ester hydrolase (NCEH), is a microsomal nCEH with high expression in murine and human macrophages. The effect of various concentrations of NaCl on its nCEH activity resembles that on endogenous nCEH activity of macrophages. RNA silencing of NCEH decreases nCEH activity at least by 50%; conversely, its overexpression inhibits the CE formation in macrophages. Immunohistochemistry reveals that NCEH is expressed in macrophage foam cells in atherosclerotic lesions. These data indicate that NCEH is responsible for a major part of nCEH activity in macrophages and may be a potential therapeutic target for the prevention of atherosclerosis.
Okazaki
Hiroaki
H
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan.
Igarashi
Masaki
M
Nishi
Makiko
M
Sekiya
Motohiro
M
Tajima
Makiko
M
Takase
Satoru
S
Takanashi
Mikio
M
Ohta
Keisuke
K
Tamura
Yoshiaki
Y
Okazaki
Sachiko
S
Yahagi
Naoya
N
Ohashi
Ken
K
Amemiya-Kudo
Michiyo
M
Nakagawa
Yoshimi
Y
Nagai
Ryozo
R
Kadowaki
Takashi
T
Osuga
Jun-ichi
J
Ishibashi
Shun
S
D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D002460:Cell Line; D002788:Cholesterol Esters / Q000235:genetics / Q000378:metabolism*; D005487:Foam Cells / Q000201:enzymology*; D020868:Gene Silencing; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D018345:Mice, Knockout; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism*
D002788:Cholesterol Esters; D002787:Sterol Esterase
J Mol Biol. 1993 Jul 20;232(2):584-99
8345525
Arterioscler Thromb Vasc Biol. 1998 Jun;18(6):991-8
9633942
Protein Eng. 1992 Apr;5(3):197-211
1409539
J Lipid Res. 2005 Jan;46(1):11-20
15548472
Arterioscler Thromb Vasc Biol. 1997 Dec;17(12):3428-32
9437189
Biochem Biophys Res Commun. 2002 Apr 12;292(4):900-3
11944899
Eur J Biochem. 2001 Apr;268(7):1899-907
11277912
Annu Rev Nutr. 2000;20:365-93
10940339
J Am Coll Cardiol. 2005 Sep 20;46(6):937-54
16168274
Biochem J. 1996 Aug 15;318 ( Pt 1):173-7
8761468
J Clin Invest. 2007 Oct;117(10):2983-92
17885686
J Biol Chem. 1981 Dec 25;256(24):12659-61
6273401
J Biol Chem. 1980 Oct 10;255(19):9344-52
7410428
J Lipid Res. 2002 Oct;43(10):1585-94
12364542
Diabetes. 2006 Jul;55(7):2091-7
16804080
Atherosclerosis. 2000 Apr;149(2):343-50
10729384
J Lipid Res. 1978 May;19(4):514-8
96199
Nucleic Acids Res. 2002 Jan 1;30(1):42-6
11752249
Science. 1988 Sep 16;241(4872):1503-6
3420405
Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):787-92
10639158
J Biol Chem. 1983 Jan 10;258(1):192-8
6848493
Biochem J. 1999 Oct 1;343 Pt 1:1-10
10493905
Diabetes. 2002 Dec;51(12):3368-75
12453888
J Biol Chem. 2000 Jul 14;275(28):21324-30
10777503
Physiol Rev. 1965 Oct;45(4):747-839
5318997
Circ Res. 2001 Sep 14;89(6):547-54
11557743
Arterioscler Thromb. 1994 Mar;14(3):443-52
8123650
Annu Rev Cell Dev Biol. 2006;22:129-57
16753029
FEBS Lett. 1989 Apr 24;247(2):205-8
2541013
Circ Res. 2006 Nov 10;99(10):1031-43
17095732
Physiol Genomics. 2000 Jan 24;2(1):1-8
11015575
J Biol Chem. 2002 Aug 30;277(35):31893-9
12036961
Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6195-200
15840715
J Lipid Res. 1993 Nov;34(11):1969-74
8263420