Absence of Nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages |
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Authors: | Motohiro Sekiya Daisuke Yamamuro Taichi Ohshiro Akira Honda Manabu Takahashi Masayoshi Kumagai Kent Sakai Shuichi Nagashima Hiroshi Tomoda Masaki Igarashi Hiroaki Okazaki Hiroaki Yagyu Jun-ichi Osuga Shun Ishibashi |
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Institution: | *Departments of Diabetes and Metabolic Diseases, University of Tokyo, Tokyo 113-8655, Japan;†Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan;§Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki 300-0395, Japan;**Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan |
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Abstract: | An excess of cholesterol and/or oxysterols induces apoptosis in macrophages, contributing to the development of advanced atherosclerotic lesions. In foam cells, these sterols are stored in esterified forms, which are hydrolyzed by two enzymes: neutral cholesterol ester hydrolase 1 (Nceh1) and hormone-sensitive lipase (Lipe). A deficiency in either enzyme leads to accelerated growth of atherosclerotic lesions in mice. However, it is poorly understood how the esterification and hydrolysis of sterols are linked to apoptosis. Remarkably, Nceh1-deficient thioglycollate-elicited peritoneal macrophages (TGEMs), but not Lipe-deficient TGEMs, were more susceptible to apoptosis induced by oxysterols, particularly 25-hydroxycholesterol (25-HC), and incubation with 25-HC caused massive accumulation of 25-HC ester in the endoplasmic reticulum (ER) due to its defective hydrolysis, thereby activating ER stress signaling such as induction of CCAAT/enhancer-binding protein-homologous protein (CHOP). These changes were nearly reversed by inhibition of ACAT1. In conclusion, deficiency of Nceh1 augments 25-HC-induced ER stress and subsequent apoptosis in TGEMs. In addition to reducing the cholesteryl ester content of foam cells, Nceh1 may protect against the pro-apoptotic effect of oxysterols and modulate the development of atherosclerosis. |
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Keywords: | KIAA1363 arylacetamide deacetylase-like 1 atherosclerosis foam cells acyl-CoA:cholesterol acyltransferase lipase/hormone-sensitive lipase oxysterols reverse cholesterol transport lipid droplets apoptosis neutral cholesterol ester hydrolase 1 endoplasmic reticulum |
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