title: Cholesteryl ester hydrolase activity is abolished in HSL-/- macrophages but unchanged in macrophages lacking KIAA1363.
abstract: Cholesteryl ester (CE) accumulation in macrophages represents a crucial event during foam cell formation, a hallmark of atherogenesis. Here we investigated the role of two previously described CE hydrolases, hormone-sensitive lipase (HSL) and KIAA1363, in macrophage CE hydrolysis. HSL and KIAA1363 exhibited marked differences in their abilities to hydrolyze CE, triacylglycerol (TG), diacylglycerol (DG), and 2-acetyl monoalkylglycerol ether (AcMAGE), a precursor for biosynthesis of platelet-activating factor (PAF). HSL efficiently cleaved all four substrates, whereas KIAA1363 hydrolyzed only AcMAGE. This contradicts previous studies suggesting that KIAA1363 is a neutral CE hydrolase. Macrophages of KIAA1363(-/-) and wild-type mice exhibited identical neutral CE hydrolase activity, which was almost abolished in tissues and macrophages of HSL(-/-) mice. Conversely, AcMAGE hydrolase activity was diminished in macrophages and some tissues of KIAA1363(-/-) but unchanged in HSL(-/-) mice. CE turnover was unaffected in macrophages lacking KIAA1363 and HSL, whereas cAMP-dependent cholesterol efflux was influenced by HSL but not by KIAA1363. Despite decreased CE hydrolase activities, HSL(-/-) macrophages exhibited CE accumulation similar to wild-type (WT) macrophages. We conclude that additional enzymes must exist that cooperate with HSL to regulate CE levels in macrophages. KIAA1363 affects AcMAGE hydrolase activity but is of minor importance as a direct CE hydrolase in macrophages.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Marlene
authors.initials: M
authors.lastname: Buchebner
authors.forename: Thomas
authors.initials: T
authors.lastname: Pfeifer
authors.forename: Nora
authors.initials: N
authors.lastname: Rathke
authors.forename: Prakash G
authors.initials: PG
authors.lastname: Chandak
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.forename: Renate
authors.initials: R
authors.lastname: Schreiber
authors.forename: Adelheid
authors.initials: A
authors.lastname: Kratzer
authors.forename: Robert
authors.initials: R
authors.lastname: Zimmermann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sattler
authors.forename: Harald
authors.initials: H
authors.lastname: Koefeler
authors.forename: Eleonore
authors.initials: E
authors.lastname: Fröhlich
authors.forename: Gerhard M
authors.initials: GM
authors.lastname: Kostner
authors.forename: Ruth
authors.initials: R
authors.lastname: Birner-Gruenberger
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Chiang
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.forename: Sanja
authors.initials: S
authors.lastname: Levak-Frank
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cravatt
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D002788:Cholesterol Esters / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D006868:Hydrolysis; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D008856:Microscopy, Fluorescence; D057057:Serine Proteases / Q000235:genetics* / Q000378:metabolism; D002787:Sterol Esterase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: D002788:Cholesterol Esters; D004075:Diglycerides; C514712:Nceh1 protein, mouse; D002787:Sterol Esterase; D057057:Serine Proteases