Identification of neutral cholesterol ester hydrolase, a key enzyme removing cholesterol from macrophages |
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Authors: | Okazaki Hiroaki Igarashi Masaki Nishi Makiko Sekiya Motohiro Tajima Makiko Takase Satoru Takanashi Mikio Ohta Keisuke Tamura Yoshiaki Okazaki Sachiko Yahagi Naoya Ohashi Ken Amemiya-Kudo Michiyo Nakagawa Yoshimi Nagai Ryozo Kadowaki Takashi Osuga Jun-ichi Ishibashi Shun |
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Affiliation: | Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan. |
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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. |
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