Cholesteryl ester hydrolase activity is abolished in HSL-/- macrophages but unchanged in macrophages lacking KIAA1363.
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.
Buchebner
Marlene
M
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Pfeifer
Thomas
T
Rathke
Nora
N
Chandak
Prakash G
PG
Lass
Achim
A
Schreiber
Renate
R
Kratzer
Adelheid
A
Zimmermann
Robert
R
Sattler
Wolfgang
W
Koefeler
Harald
H
Fröhlich
Eleonore
E
Kostner
Gerhard M
GM
Birner-Gruenberger
Ruth
R
Chiang
Kyle P
KP
Haemmerle
Guenter
G
Zechner
Rudolf
R
Levak-Frank
Sanja
S
Cravatt
Benjamin
B
Kratky
Dagmar
D
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
D002788:Cholesterol Esters; D004075:Diglycerides; C514712:Nceh1 protein, mouse; D002787:Sterol Esterase; D057057:Serine Proteases