Journal
JOURNAL OF LIPID RESEARCH
Volume 55, Issue 10, Pages 2082-2092Publisher
ELSEVIER
DOI: 10.1194/jlr.M050864
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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Funding
- Japan Society for the Promotion of Science
- Ministry of Education and Science
- Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO)
- KEIRIN RACE
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Grants-in-Aid for Scientific Research [26253009, 26870533] Funding Source: KAKEN
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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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