title: Absence of Nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages.
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.
authors.affiliation: Departments of Diabetes and Metabolic Diseases, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sekiya
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamamuro
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Ohshiro
authors.affiliation: Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki 300-0395, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Honda
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Departments of Diabetes and Metabolic Diseases, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kumagai
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Kent
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Nagashima
authors.affiliation: Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomoda
authors.affiliation: Departments of Diabetes and Metabolic Diseases, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Igarashi
authors.affiliation: Departments of Diabetes and Metabolic Diseases, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Okazaki
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yagyu
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Osuga
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Ishibashi
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D006888:Hydroxycholesterols / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: C497250:Ddit3 protein, mouse; D006888:Hydroxycholesterols; D051742:Transcription Factor CHOP; C007997:25-hydroxycholesterol; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase; C514712:Nceh1 protein, mouse; D002787:Sterol Esterase
keywords: KIAA1363; acyl-CoA:cholesterol acyltransferase; apoptosis; arylacetamide deacetylase-like 1; atherosclerosis; endoplasmic reticulum; foam cells; lipase/hormone-sensitive lipase; lipid droplets; neutral cholesterol ester hydrolase 1; oxysterols; reverse cholesterol transport