title: Ablation of neutral cholesterol ester hydrolase 1 accelerates atherosclerosis.
abstract: 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.
authors.affiliation: Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sekiya
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Osuga
authors.forename: Shuichi
authors.initials: S
authors.lastname: Nagashima
authors.forename: Taichi
authors.initials: T
authors.lastname: Ohshiro
authors.forename: Masaki
authors.initials: M
authors.lastname: Igarashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okazaki
authors.forename: Manabu
authors.initials: M
authors.lastname: Takahashi
authors.forename: Fumiko
authors.initials: F
authors.lastname: Tazoe
authors.forename: Taeko
authors.initials: T
authors.lastname: Wada
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ohta
authors.forename: Mikio
authors.initials: M
authors.lastname: Takanashi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kumagai
authors.forename: Makiko
authors.initials: M
authors.lastname: Nishi
authors.forename: Satoru
authors.initials: S
authors.lastname: Takase
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yagyu
authors.forename: Ken
authors.initials: K
authors.lastname: Ohashi
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
mesh_terms: 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*
chemical_list: D001057:Apolipoproteins E; D002788:Cholesterol Esters; D002784:Cholesterol; C514712:Nceh1 protein, mouse; D002787:Sterol Esterase; D057057:Serine Proteases