title: Identification of neutral cholesterol ester hydrolase, a key enzyme removing cholesterol from macrophages.
abstract: 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.
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okazaki
authors.forename: Masaki
authors.initials: M
authors.lastname: Igarashi
authors.forename: Makiko
authors.initials: M
authors.lastname: Nishi
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sekiya
authors.forename: Makiko
authors.initials: M
authors.lastname: Tajima
authors.forename: Satoru
authors.initials: S
authors.lastname: Takase
authors.forename: Mikio
authors.initials: M
authors.lastname: Takanashi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ohta
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tamura
authors.forename: Sachiko
authors.initials: S
authors.lastname: Okazaki
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.forename: Ken
authors.initials: K
authors.lastname: Ohashi
authors.forename: Michiyo
authors.initials: M
authors.lastname: Amemiya-Kudo
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Osuga
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
mesh_terms: 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*
chemical_list: D002788:Cholesterol Esters; D002787:Sterol Esterase
references.citation: J Mol Biol. 1993 Jul 20;232(2):584-99
references.pmid: 8345525
references.citation: Arterioscler Thromb Vasc Biol. 1998 Jun;18(6):991-8
references.pmid: 9633942
references.citation: Protein Eng. 1992 Apr;5(3):197-211
references.pmid: 1409539
references.citation: J Lipid Res. 2005 Jan;46(1):11-20
references.pmid: 15548472
references.citation: Arterioscler Thromb Vasc Biol. 1997 Dec;17(12):3428-32
references.pmid: 9437189
references.citation: Biochem Biophys Res Commun. 2002 Apr 12;292(4):900-3
references.pmid: 11944899
references.citation: Eur J Biochem. 2001 Apr;268(7):1899-907
references.pmid: 11277912
references.citation: Annu Rev Nutr. 2000;20:365-93
references.pmid: 10940339
references.citation: J Am Coll Cardiol. 2005 Sep 20;46(6):937-54
references.pmid: 16168274
references.citation: Biochem J. 1996 Aug 15;318 ( Pt 1):173-7
references.pmid: 8761468
references.citation: J Clin Invest. 2007 Oct;117(10):2983-92
references.pmid: 17885686
references.citation: J Biol Chem. 1981 Dec 25;256(24):12659-61
references.pmid: 6273401
references.citation: J Biol Chem. 1980 Oct 10;255(19):9344-52
references.pmid: 7410428
references.citation: J Lipid Res. 2002 Oct;43(10):1585-94
references.pmid: 12364542
references.citation: Diabetes. 2006 Jul;55(7):2091-7
references.pmid: 16804080
references.citation: Atherosclerosis. 2000 Apr;149(2):343-50
references.pmid: 10729384
references.citation: J Lipid Res. 1978 May;19(4):514-8
references.pmid: 96199
references.citation: Nucleic Acids Res. 2002 Jan 1;30(1):42-6
references.pmid: 11752249
references.citation: Science. 1988 Sep 16;241(4872):1503-6
references.pmid: 3420405
references.citation: Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):787-92
references.pmid: 10639158
references.citation: J Biol Chem. 1983 Jan 10;258(1):192-8
references.pmid: 6848493
references.citation: Biochem J. 1999 Oct 1;343 Pt 1:1-10
references.pmid: 10493905
references.citation: Diabetes. 2002 Dec;51(12):3368-75
references.pmid: 12453888
references.citation: J Biol Chem. 2000 Jul 14;275(28):21324-30
references.pmid: 10777503
references.citation: Physiol Rev. 1965 Oct;45(4):747-839
references.pmid: 5318997
references.citation: Circ Res. 2001 Sep 14;89(6):547-54
references.pmid: 11557743
references.citation: Arterioscler Thromb. 1994 Mar;14(3):443-52
references.pmid: 8123650
references.citation: Annu Rev Cell Dev Biol. 2006;22:129-57
references.pmid: 16753029
references.citation: FEBS Lett. 1989 Apr 24;247(2):205-8
references.pmid: 2541013
references.citation: Circ Res. 2006 Nov 10;99(10):1031-43
references.pmid: 17095732
references.citation: Physiol Genomics. 2000 Jan 24;2(1):1-8
references.pmid: 11015575
references.citation: J Biol Chem. 2002 Aug 30;277(35):31893-9
references.pmid: 12036961
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 26;102(17):6195-200
references.pmid: 15840715
references.citation: J Lipid Res. 1993 Nov;34(11):1969-74
references.pmid: 8263420