Ablation of neutral cholesterol ester hydrolase 1 accelerates atherosclerosis.
Cholesterol ester (CE)-laden macrophage foam cells are the hallmark of atherosclerosis, and the hydrolysis of intracellular CE is one of the key steps in foam cell formation. Although hormone-sensitive lipase (LIPE) and cholesterol ester hydrolase (CEH), which is identical to carboxylsterase 1 (CES1, hCE1), were proposed to mediate the neutral CE hydrolase (nCEH) activity in macrophages, recent evidences have suggested the involvement of other enzymes. We have recently reported the identification of a candidate, neutral cholesterol ester hydrolase 1(Nceh1). Here we demonstrate that genetic ablation of Nceh1 promotes foam cell formation and the development of atherosclerosis in mice. We further demonstrate that Nceh1 and Lipe mediate a comparable degree of nCEH activity in macrophages and together account for most of the activity. Mice lacking both Nceh1 and Lipe aggravated atherosclerosis in an additive manner. Thus, Nceh1 is a promising target for the treatment of atherosclerosis.
Sekiya
Motohiro
M
Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Osuga
Jun-Ichi
J
Nagashima
Shuichi
S
Ohshiro
Taichi
T
Igarashi
Masaki
M
Okazaki
Hiroaki
H
Takahashi
Manabu
M
Tazoe
Fumiko
F
Wada
Taeko
T
Ohta
Keisuke
K
Takanashi
Mikio
M
Kumagai
Masayoshi
M
Nishi
Makiko
M
Takase
Satoru
S
Yahagi
Naoya
N
Yagyu
Hiroaki
H
Ohashi
Ken
K
Nagai
Ryozo
R
Kadowaki
Takashi
T
Furukawa
Yusuke
Y
Ishibashi
Shun
S
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D005487:Foam Cells / Q000166:cytology / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D057057:Serine Proteases / Q000235:genetics / Q000502:physiology*; D002787:Sterol Esterase / Q000235:genetics / Q000502:physiology*
D001057:Apolipoproteins E; D002788:Cholesterol Esters; D002784:Cholesterol; C514712:Nceh1 protein, mouse; D002787:Sterol Esterase; D057057:Serine Proteases